BASIC PHARMACOKINETICS - CHAPTER 8: Bioavailability

Basic Pharmacokinetics REV. 99.4.25 8-1Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/

CHAPTER 8 Bioavailability, Bioequivalence, and Drug Selection

Author: Rasma CheresonReviewer: Umesh Banakar

OBJECTIVES

1. Given sufficient data to compare an oral product with another oral product or an IV product, the student will estimate (III) the bioavailability (compare AUCs) and judge (VI) professional acceptance of the product with regard to bioequivalence (evaluate (VI) AUC, and ).

2. The student will write (V) a professional consult using the above calculations.

3. The student will be able to calculate (III) the absolute bioavailability of drug prod-ucts.

4. The student will be able to discuss (II) the various factors affecting bioavailability.

5. The student will be able to discuss (II) the various methods of assessing bioavail-ablity.

6. The student will be able to discuss (II) In Vivo / In Vitro Correlations.

7. The student will be able to enumerate (II) FDA requirements regarding bioequiva-lence.

8. The student shall be able to utilize (III) the FDA “Orange Book” to make drug product selections.

9. The student shall be able to discuss (II) and utilize (III) reasonalble guidelines regarding drug product selections.

Tp Cp( )max

Bioavailability, Bioequivalence, and Drug Selection


8.1 Bioavailability, Bioequivalence and Drug Product Selection

Bioavailability and bioequivalence of drug products, and drug product selectionhave emerged as critical issues in pharmacy and medicine during the last threedecades. Concern about lowering health care costs has resulted in a tremendousincrease in the use of generic drug products; currently about one half of all pre-scriptions written are for drugs that can be substituted with a generic product (1).Over 80% of the approximately 10,000 prescription drugs available in 1990 wereavailable from more than one source (2). With the increasing availability and useof generic drug products, health care professionals are confronted with anever-larger array of multisource products from which they must select those thatare therapeutically equivalent.

This phenomenal growth of the generic pharmaceutical industry and the abun-dance of multisource products have prompted some questions among many healthprofessionals and scientists regarding the therapeutic equivalency of these prod-ucts, particularly those in certain critical therapeutic categories such as anticonvul-sants and cardiovasculars (1, 3-5). Inherent in the currently accepted guidelinesfor product substitution is the assumption that a generic drug considered to bebioequivalent to a brand-name drug will elicit the same clinical effect. As straight-forward as this statement regarding bioequivalence appears to be, it has generateda great deal of controversy among scientists and professionals in the health carefield. Numerous papers in the literature indicate that there is concern that the cur-rent standards for approval of generic drugs may not always ensure therapeuticequivalence (6-18).

The availability of different formulations of the same drug substance given at thesame strength and in the same dosage form poses a special challenge to health careprofessionals, making these issues very relevant to pharmacists in all practice set-tings. Since pharmacists play an important role in product-selection decisions,they must have an understanding of the principles and concepts of bioavailabilityand bioequivalence.

8.1.1 RELATIVE AND ABSOLUTE BIOAVAILABILITY

Bioavailability is a pharmacokinetic term that describes the rate and extent towhich the active drug ingredient is absorbed from a drug product and becomesavailable at the site of drug action. Since pharmacologic response is generallyrelated to the concentration of drug at the receptor site, the availability of a drugfrom a dosage form is a critical element of a drug product's clinical efficacy. How-ever, drug concentrations usually cannot be readily measured directly at the site of



action. Therefore, most bioavailability studies involve the determination of drugconcentration in the blood or urine. This is based on the premise that the drug atthe site of action is in equilibrium with drug in the blood. It is therefore possible toobtain an indirect measure of drug response by monitoring drug levels in the bloodor urine. Thus, bioavailability is concerned with how quickly and how much of adrug appears in the blood after a specific dose is administered. The bioavailabilityof a drug product often determines the therapeutic efficacy of that product since itaffects the onset, intensity and duration of therapeutic response of the drug. Inmost cases one is concerned with the extent of absorption of drug, (that is, the frac-tion of the dose that actually reaches the bloodstream) since this represents the"effective dose" of a drug. This is generally less than the amount of drug actuallyadministered in the dosage form. In come cases, notably those where acute condi-tions are being treated, one is also concerned with the rate of absorption of a drug,since rapid onset of pharmacologic action is desired. Conversely, these areinstances where a slower rate of absorption is desired, either to avoid adverseeffects or to produce a prolonged duration of action.

"Absolute" bioavailability, F, is the fraction of an administered dose which actuallyreaches the systemic circulation, and ranges from F = 0 (no drug absorption) to F =1 (complete drug absorption). Since the total amount of drug reaching the sys-temic circulation is directly proportional to the area under the plasma drug concen-tration as a function of time curve (AUC), F is determined by comparing therespective AUCs of the test product and the same dose of drug administered intra-venously. The intravenous route is the reference standard since the dose is, by def-inition, completely available.

(EQ 8-1)

(where AUCEV and AUCIV are, respectively, the area under the plasma concentra-tion-time curve following the extravascular and intravenous administration of agiven dose of drug. Knowledge of F is needed to determine an appropriate oraldose of a drug relative to an IV dose.

"Relative" or “Comparative” bioavailability refers to the availability of a drugproduct as compared to another dosage form or product of the same drug given inthe same dose. These measurements determine the effects of formulation differ-ences on drug absorption. The relative bioavailability of product A compared toproduct B, both products containing the same dose of the same drug, is obtained bycomparing their respective AUCs.

(EQ 8-2)

FAUCev

AUCiv

-----------------=

RelativeBioavailabiltyAUCA

AUCB

---------------=



where drug product B is the reference standard. When the bioavailability of ageneric product is considered, it is usually the relative bioavailability that isreferred to. A more general form of the equation results from considering the pos-sibility of different doses,

(EQ 8-3)

The difference between absolute and relative bioavailability is illustrated by thefollowing hypothetical example. Assume that an intravenous injection (ProductA) and two oral dosage forms (Product B and Product C), all containing the samedose of the same drug, are given to a group of subjects in a crossover study. Fur-thermore, suppose each product gave the values for AUC indicated in Table 8-1 onpage 4.

TABLE 8-1. Data for Absolute and Relative Bioavailability

The F for Product B and Product C is 50% (F = 0.5) and 40% (F = 0.4), respec-tively. However, when the two oral products are compared, the relative bioavail-ability of Product C as compared to Product B is 80%.

8.1.2 FACTORS INFLUENCING BIOAVAILABILITY

Before the therapeutic effect of an orally administered drug can be realized, thedrug must be absorbed. The systemic absorption of an orally administered drug ina solid dosage form is comprised of three distinct steps:

1. disintegration of the drug product

2. dissolution of the drug in the fluids at the absorption site

3. transfer of drug molecule across the membrane lining the gastrointestinal tract into the systemic circulation.

Drug Product Area Under the Curve (mcg/ml) x hr

A Intravenous injection 100

B Oral dosage form, brand or reference standard 50

C Oral dosage form, generic Product 40

ComparativeBioavailability

AUCGeneric

DoseGeneric

-----------------------------

AUCBrand

DoseBrand

-------------------------

-----------------------------=



Any factor that affects any of these three steps can alter the drug's bioavailabilityand thereby its therapeutic effect. While there are more than three dozen of thesefactors that have been identified (19-38), the more significant ones are summarizedhere.

The various factors that can influence the bioavailability of a drug can be broadlyclassified as dosage form-related or patient-related. Some of these factors arelisted in Table 8-2 on page 5 and Table 8-3 on page 5, respectively.

TABLE 8-2 Bioavailability Factors related to the dosage form

TABLE 8-3 Bioavailability Factors Related to the patient

The physical and chemical characteristics of a drug as well as its formulation areof prime importance in bioavailability because they can affect not only the absorp-tion characteristics of the drug but also its stability. Since a drug must be dissolvedto be absorbed, its rate of dissolution from a given product must influence its rateof absorption. This is particularly the case for sparingly soluble drugs. All the fac-tors listed in Table 8-2 on page 5 can alter the dissolution rate of the drug, its bio-availability, and ultimately, its therapeutic performance.

One of the more important factors that affects the dissolution rate of slowly dis-solving substances is the surface area of the dissolving solid (39). Peak blood lev-els occurred much faster with the smaller particles than the larger ones, primarily

Physicochemical properties of the drug Formulation and manufacturing variables

Particle size

Crystalline structure

Degree of hydration of crystal

Salt or ester form

Amount of disintegrant

Amount of lubricant

Special coatings

Nature of diluent

Compression force

Physiologic factors Interactions with other substances

Variations in absorption power along GI tract

Variations in pH of GI fluids

Gastric emptying rate

Intestinal motility

Perfusion of GI tract

Presystemic and first-pass metabolism

Age, sex, weight

Disease states

Food

Fluid volume

Other drugs



as a result of their faster dissolution rate. Particle size can also have a significanteffect on AUC(40). Serum levels of phenytoin after administration of equal dosescontaining micronized (formulation G) and conventional (formulation F) drugwere measured. Based on the AUC, almost twice as much phenytoin wasabsorbed after the micronized preparation (40).

There are numerous reports of the effects of formulation and processing variableson the dissolution of active ingredients from drug products; an apparently inertingredient may affect drug absorption. For example, magnesium stearate, a lubri-cant, commonly used in tablet and capsule formulations, is water-insoluble andwater-repellent. Its hydrophobic nature tends to retard drug dissolution by pre-venting contact between the solid drug and the aqueous GI fluids. Thus, increas-ing the amount of magnesium stearate in the formulation results in a slowerdissolution rate of the drug, and decreased bioavailability(34) .

The nature of the dosage form itself may have an effect on drug absorption charac-teristics. The major pharmaceutical dosage forms for oral use are listed in Table 8-4 on page 6 in order of decreasing bioavailability of their active ingredients. Thedecreasing bioavailability is related to the number of steps involved in the absorp-tion process following administration. The greater the number of steps a productmust undergo before the final absorption step, the slower is the availability and thegreater is the potential for bioavailability differences to occur. Thus, solutions(elixirs, syrups, or simple solutions) generally result in faster and more completeabsorption of drug, since a dissolution step is not required. Enteric-coated tablets,on the other hand, do not even begin to release the drug until the tablets emptyfrom the stomach, resulting in poor and erratic bioavailability.

TABLE 8-4 Bioavailability and oral Dosage Forms

Bioavailability studies with pentobarbital from various dosage forms show theabsorption rate of pentobarbital after administration in various oral dosage formsdecreased in the following order: aqueous solution > aqueous suspension of thefree acid > capsule of the sodium salt > tablet of the free acid (41).

In addition to the dosage form-related factors identified above, bioavailability mayalso be affected by a variety of physiologic and clinical factors related to thepatient (Table 8-3 on page 5). Considerable inter-subject differences in the bio-

Fastest availability

Slowest availability

Solutions

Suspensions

Capsules

Tablets

Coated tablets

Controlled-release formulations



availability of some drugs have been observed. These can often be attributed toindividual variations in such factors as GI motility, disease state and concomi-tantly-administered food or drugs.

One example of the myriad of physiologic factors that can affect the bioavailabilityof an orally-administered drug is a patient's gastric emptying rate. Since the prox-imal small intestine is the optimum site for drug absorption, a change in the stom-ach emptying rate is likely to alter the rate, and possibly the extent, of drugabsorption. Any factor that slows the gastric emptying rate may thus prolong theonset time for drug action and reduce the therapeutic efficacy of drugs that are pri-marily absorbed from the small intestine. In addition, a delay in gastric emptyingcould result in extensive decomposition and reduced bioavailability of drugs thatare unstable in the acidic media of the stomach (e.g. penicillins and erythromycin).

Differences in stomach emptying among individuals have been implicated as amajor cause of variations in the bioavailability of some drugs, particularly thosewith acid-resistant enteric coatings. In a study (42), after the administration of 1.5g acetaminophen to 14 patients, the maximum plasma concentration ranged from7.4 to 37 mcg/ml, and the time to reach the maximum concentration ranged from30 to 180 minutes. Both these parameters of bioavailability were linearly relatedto the gastric emptying half-life found in each patient.

There are numerous factors that affect gastric emptying rate (Table 8-5 on page 8)(43). Factors such as a patient's emotional state, certain drugs, type of foodingested and even a patient's posture can alter the time course and extent of drugabsorption.



TABLE 8-5 Factors influencing Gastric Emptying Rate

Since drugs are generally administered to patients who are ill, it is important toconsider the effects of the disease process on the bioavailability of the drug. Dis-ease states, particularly those involving the GI tract, such as celiac disease, Crohn'sdisease, achlorhydria, and hypermotility syndromes can certainly alter the absorp-tion of a drug (32). In addition, some diseases concerning the cardiovascular sys-tem and the liver may also alter circulating drug levels after oral dosing.

Drugs are frequently taken with food, and patients often use mealtimes to remindthem to take their medications. However, food can have a significant effect on thebioavailability of drugs. The influence of food on drug absorption has been recog-

FACTOR INFLUENCE ON GASTRIC

EMPTYING RATE

Increased viscosity of stomach contents decreased

Body position

lying on left side decreased

Emotional state

stress

depression

anxiety

increased or decreased

decreased

increased

Activity, exercise decreased

Type of meal

fatty acids, fats

carbohydrates

amino acids

decreased

decreased

decreased

pH of stomach contents

decreased

increased

decreased

increased

Disease states

gastric ulcers

Crohn's disease

hypothyroidism

hyperthyroidism

decreased

decreased

decreased

increased

Drugs

atropine

propantheline

narcotic analgesics

amitriptyline

metoclopramide

decreased

decreased

decreased

decreased

increased



nized for some time, and several reviews have been published on the influence offood on drug bioavailability (30-32, 36, 44). Food may influence drug absorptionindirectly, through physiological changes in the GI tract produced by the food,and/or directly, through physical or chemical interactions between the drug mole-cules and food components. When food is ingested, stomach emptying is delayed,gastric secretions are increased, stomach pH is altered, and splanchnic blood flowmay increase. These may all affect bioavailability of drugs. Food may also inter-act directly with drugs, either chemically (e.g. chelation) or physically, by adsorb-ing the drug or acting as a barrier to absorption. In general, gastrointestinalabsorption of drugs is favored by an empty stomach, but the nature of drug-foodinteractions is complex and unpredictable; drug absorption may be reduced,delayed, enhanced or unaffected by the presence of food. Table 8-6 on page 9summarizes some of the studies that have indicated the effect of food on the bio-availability of a variety of drugs.

TABLE 8-6 Effect of Food on Drug Absorption

The effect of food and type of diet on the bioavailability of erythromycin is shownin a study by Welling (45). The absorption of the antibiotic is significantlyreduced when it is administered with food compared with its absorption under fast-ing conditions. This reduced absorption is primarily a result of degradation of theacid-labile erythromycin due to prolonged retention in the stomach.

Delayed absorption due to food has been demonstrated in the case of cephradine ina study by Mischler (46). Similar results have been observed with other oral ceph-alosporins.

Some drugs demonstrate enhanced bioavailability in the presence of food. Thishas been attributed to a variety of factors, including improved compound solubilityand more time for dissolution because of delayed gastric emptying. In the case of

Reduced Absorption Delayed Absorption Increased Absorption

Ampicillin

Aspirin

Atenolol

Captopril

Erythromycin

Ethanol

Hydrochlorothiazide

Penicillins

Tetracyclines (most)

Acetaminophen

Aspirin

Cephalosporins (most)

Diclofenac

Digoxin

Furosemide

Nitrofurantoin

Sulfadiazine

Sulfisoxazole

Chlorothiazide

Diazepam

Griseofulvin

Hydralazine

Labetalol

Metoprolol

Nitrofurantoin

Propranolol

Riboflavin

Source: Ref. 32



highly metabolized agents, such as propranolol and metoprolol, the enhancedavailability may be due to increased splanchnic blood flow causing reducedfirst-pass clearance. The circulating levels of these drugs dosed under fasting andnon-fasting conditions have been presented in a study by Melander (47).

The volume of fluid with which an orally administered dose is taken can also affecta drug's bioavailability. Drug administration with a larger fluid volume will gener-ally improve its dissolution characteristics and may also result in more rapid stom-ach emptying. Thus, more efficient and more reliable drug absorption can beexpected when an oral dosage form is administered with a larger volume of fluid.(45) .

Interactions between drugs can have a significant effect on the bioavailability ofone or both drugs. Such interactions may be direct, as in chelation of tetracyclineby polyvalent metal ions in antacids or the adsorption of digoxin bycholestyramine resin, or indirect, as with the increased rate of acetaminophenabsorption due to the increased gastric emptying rate produced by metoclopra-mide. Most of the reported drug-drug interactions have resulted in a reduction inthe rate and/or extent of drug absorption, the most frequent causes being complex-ing of a drug with other substances, reduced GI motility and alterations in drugionization (24, 30, 32, 48, 49). Table 8-7 on page 10 summarizes the major mech-anisms of GI drug interactions affecting bioavailability.

TABLE 8-7 Drug interactions affecting absorption

An example of a direct interaction between drugs affecting bioavailability is theinteraction between iron and tetracycline. This is a well-documented and clini-cally significant interaction which can result in a dramatic reduction in serum con-centration of tetracycline (50).

The above potential sources of alteration in a drug's bioavailability must be kept inmind when attempting to evaluate the relative performance of drug products on the

1. Change in gastric or intestinal pH

2. Change in gastrointestinal motility

3. Change in gastrointestinal perfusion

4. Interference with mucosal function (drug-induced malabsorption syndromes)

5. Chelation

6. Exchange resin binding

7. Aadsorption

8. Solution in poorly absorbable liquid

Source: Ref. 23



basis of studies performed with healthy human volunteers. These studies are gen-erally performed under tightly-controlled fasting conditions in the absence of otherdrugs. In practice, however, drugs are seldom taken under such ideal conditions,and the factors leading to changes in drug absorption must be taken into consider-ation.

8.1.3 METHODS OF ASSESSING BIOAVAILABILITY

Bioavailability testing is a means of predicting the clinical efficacy of a drug; theestimation of the bioavailability of a drug in a given dosage form is direct evidenceof the efficiency with which a dosage form performs its intended therapeutic func-tion.

The bioavailability of a drug substance formulated into a pharmaceutical productis fundamental to the goals of dosage form design and essential for the clinical effi-cacy of the medication. Thus, bioavailability testing, which measures the rate andextent of drug absorption, is a way to obtain evidence of the therapeutic utility of adrug product. Bioavailability determinations are performed by drug manufacturersto ensure that a given drug product will get the therapeutic agent to its site ofaction in an adequate concentration. Bioavailability studies are also carried out tocompare the availability of a drug substance from different dosage forms or fromthe same dosage form produced by different manufacturers.

In-vivo methods One method for assessing the bioavailability of a drug product is through the dem-onstration of a clinically significant effect. However, such clinical studies arecomplex, expensive, time-consuming and require a sensitive and quantitative mea-sure of the desired response. Further, response is often quite variable, requiring alarge test population. Practical considerations, therefore, preclude the use of thismethod except in initial stages of development while proving the efficacy of a newchemical entity.

Quantification of pharmacologic effect is another possible way to assess a drug'sbioavailability. This method is based on the assumption that a given intensity ofresponse is associated with a particular drug concentration at the site of action;e.g., variation of miotic response intensity can be directly related to the oral doseof chlorpromazine. However, monitoring of pharmacologic data is often difficult,precision and reproducibility are difficult to establish, and there are only a limitednumber of pharmacologic effects (e.g. heart rate, body temperature, blood sugarlevels) that are applicable to this method.

Because of these limitations, alternative methods have been developed to predictthe therapeutic potential of a drug. The current method to assess the clinical per-formance of a drug involves measurement of the drug concentrations in the blood



or urine. In such studies a single dose of the drug product is administered to apanel of normal, healthy adult (18- to 35-year old) subjects. Blood and/or urinesamples are collected over a period of time following administration and are ana-lyzed for drug content. Based on the blood concentration as a function of timeand/or urinary excretion profile, inferences are drawn regarding the rate and extentof absorption of the drug. These studies are relatively easy to conduct and requirea limited number of subjects.

Blood level studies- Blood level studies are the most common type of human bioavailability studies,and are based on the assumption that there is a direct relationship between the con-centration of drug in blood or plasma and the concentration of drug at the site ofaction. By monitoring the concentration in the blood, it is thus possible to obtainan indirect measure of drug response. Following the administration of a singledose of a medication, blood samples are drawn at specific time intervals and ana-lyzed for drug content. A profile is constructed showing the concentration of drugin blood at the specific times the samples were taken . The key parameters to noteare:

1. AUC , The area under the plasma concentration-time curve, The AUC is proportional to the

total amount of drug reaching the systemic circulation, and thus characterizes the extent of absorption.

2. Cmax , The maximum drug concentration. The maximum concentration of drug in the plasma

is a function of both the rate and extent of absorption. Cmax will increase with an increase in the dose, as well as with an increase in the absorption rate.

3. Tmax , The time at which the Cmax occurs. The Tmax reflects the rate of drug absorption, and decreases as the absorption rate increases.

Bioavailability (the rate and extent of drug absorption) is generally assessed by thedetermination of these three parameters.

Since the AUC is representative of, and proportional to, the total amount of drugabsorbed into the circulation, it is used to quantitate the extent of drug absorption.The calculation of AUC has been discussed in Chapter 4. A variety of pharmacok-inetic methods have been suggested for the calculation of absorption rates (51-56).For clinical purposes, it is generally sufficient to determine Cmax and Tmax. If allother factors are constant, such as the extent of absorption and rate of elimination,then Cmax is proportional to the rate of absorption and Tmax is inversely propor-tional to the absorption rate. Thus, the faster the absorption of a drug the higherthe maximum concentration will be and the less time it will take to reach the max-imum concentration.

Urinary Excretion Data - An alternative bioavailability study measures the cumulative amount of unchangeddrug excreted in the urine. These studies involve collection of urine samples andthe determination of the total quantity of drug excreted in the urine as a function of

∞0



time. These studies are based on the premise that urinary excretion of theunchanged drug is directly proportional to the plasma concentration of total drug.Thus, the total quantity of drug excreted in the urine is a reflection of the quantityof drug absorbed from the gastrointestinal tract. Consider the following example:two products, A and B, each containing 100 mg of the same drug are administeredorally. A total of 80 mg of drug is recovered in the urine from Product A, but only40 mg is recovered from Product B. This indicates that twice as much drug wasabsorbed from Product A as from Product B. (The fact that neither productresulted in excretion of the entire dose might be due to the existence of other routesof elimination, e.g. metabolism).

This technique of studying bioavailability is most useful for those drugs that arenot extensively metabolized prior to urinary elimination. As a rule-of-thumb,determination of bioavailability using urinary excretion data should be conductedonly if at least 20% of a dose is excreted unchanged in the urine after an IV dose(56). Other conditions which must be met for this method to give valid resultsinclude:

1. the fraction of drug entering the bloodstream and being excreted intact by the kidneys must remain constant.

2. collection of the urine has to continue until all the drug has been completely excreted (five times

the half-life1).

Urinary excretion data are primarily useful for assessing extent of drug absorption,although the time course for the cumulative amount of drug excreted in the urinecan also be used to estimate the rate of absorption. In practice, these estimates aresubject to a high degree of variability, and are less reliable than those obtainedfrom plasma concentration-time profiles (57). Thus, urinary excretion of drug isnot recommended as a substitute for blood concentration data; rather, these studiesshould be used in conjunction with blood level data for confirmatory purposes.

Single-dose versus Multiple-Dose-

Most bioavailability evaluations are made on the basis of single-dose administra-tion. The argument has been made that single doses are not representative of theactual clinical situation, since in most instances, patients require repeated adminis-tration of a drug. When a drug is administered repeatedly at fixed intervals, withthe dosing frequency less than five half-lives, drug will accumulate in the body andeventually reach a plateau, or a steady-state

At steady-state, the amount of drug eliminated from the body during one dosinginterval is equal to the available dose (rate in = rate out); therefore, the area underthe curve during a dosing interval at steady-state is equal to the total area under thecurve obtained when a single dose is administered. This AUC can therefore be

1. Half life is defined as the length of time required to lose 50% of the drug in the body, assuming first order elimination.



used to assess the extent of absorption of the drug, as well as its absolute and rela-tive bioavailability.

Multiple-dose administration has several advantages over single-dose bioavailabil-ity studies, as well as some limitations. These are summarized in Table 8-8 onpage 14 (54, 59).

TABLE 8-8 Multiple dose vs. single dose studies in bioavailability studies

When a drug obeys linear, first-order kinetics, it is possible to estimate the resultsthat would be obtained during multiple dosing from single-dose studies. Projec-tion is easily made with regard to the extent of absorption, using the AUC follow-ing a single dose. Results from bioequivalence studies indicate that conclusions onthe extent of absorption as assessed by the AUC can be made equally well on thebasis of a single or multiple dose study (60). Assessing the rate of absorption dur-ing multiple-dosing from single-dose studies has presented a greater problem.Although a number of single-dose characteristics have been suggested as indica-tors of rate of absorption during multiple dosing (e.g. percent peak-trough fluctua-tion and percent peak-trough swing), results of bioequivalence studies indicate thatonly the plateau time (the time during which the concentration exceeds 75% of themaximum concentration, t 75% Cmax) and the residual concentration at the end ofthe dose interval produce consistent results in assessing the rate of absorption insingle- and multiple-dose studies (54, 61).

In the case of drugs exhibiting nonlinear kinetics, establishing a linear relationshipbetween single- and multiple-dose bioavailability data has proven to be a difficulttask. Thus, it has been recommended that for drugs with either saturable elimina-tion or a nonlinear first-pass effect, steady-state studies be carried out to assesstheir bioavailability (62).

Advantages:

• Eliminates the need to extrapolate the plasma concentration profiles to obtain the total AUC after a single dose

• Eliminates the need for a long wash-out period between doses

• More closely reflects the actual clinical use of the drug

• Allows blood levels to be measured at the same concentrations encountered therapeutically

• Because blood levels tend to be higher than in the single-dose method, quantitative determina-tion is easier and more reliable

• Saturable pharmacokinetics, if present, can be more readily detected at steady-state

Limitations:

• Requires more time to complete

• More difficult and costly to conduct (requiring prolonged monitoring of subjects

• Greater problems with compliance control

• Greater exposure of subjects to the test drug, increasing the potential for adverse reactions



8.1.4 STUDY DESIGN

Bioavailability studies involve the administration of the test dosage form to a panelof subjects, after which blood and/or urine samples are collected and analyzed fordrug content. Based on the concentration profile of the drug, a judgement is maderegarding the rate and extent of absorption of the drug. Normally, the study is con-ducted in a group of healthy, male subjects who are of normal height and weight,and range in age from 18 to 35 years (6). Questions have been raised regarding theextent to which such a population reflects the performance of a given drug productin a actual patient population. At first glance, it would seem that bioavailabilityshould be determined in patients actually suffering from the disease for which thedrug is intended, or in patients representative of the age and sex of subjects whowould be using the drug. However, there are several very good reasons for usinghealthy volunteers rather than patients. In bioavailability studies, it is assumedthat there are no physiologic changes in the subjects during the course of the study.If actual patients were used, this would not be a valid assumption, due to possiblechanges in the disease state. Another potential problem with using patients is thatmany patients take more than one drug. This could result in a drug-drug interac-tion which could influence the bioavailability of the test drug. In addition, diet andfluid volume intake, both of which can influence a drug's bioavailability are moredifficult to control in a patient population than in a panel of healthy test subjects.In general, it is more difficult with patients to have a standardized set of conditionswhich are necessary for a dependable bioavailability study. However, it must berecognized that factors that may affect a drug's performance in a patient populationmay not be detected in a group of healthy subjects. Thus, it is best to conduct aseparate study in patients to determine if the disease, for which the drug is intendedto be used, alters the bioavailability of the drug.

Other important considerations in the methodology of a bioavailability study aresample size, period of trial, and sampling. For statistical purposes, twelve subjectsare considered to be a minimum sample size. Otherwise there will not be enoughdata to draw valid conclusions (63). The bioavailability testing period should be ofa sufficient length of time to ensure that drug absorption has been completed. Thislength of time is at least three times the half-life of the drug; generally a period offour to five times the half-life is used (63, 64). Blood samples should be takenwith sufficient frequency to permit an accurate determination of tmax, Cmax andAUC.

8.1.5 IN-VITRO DISSOLUTION AND BIOAVAILABILITY

Pharmaceutical scientists have for many years been attempting to establish a corre-lation between some physicochemical property of a dosage form and the biological



availability of the drug from that dosage form. The term commonly used todescribe this relationship is "in-vitro/in-vivo correlation" (65). Specifically, it isfelt that if such a correlation could be established, it would be possible to usein-vitro data to predict a drug's in-vivo bioavailability. This would drasticallyreduce, or in some cases, completely eliminate the need for bioavailability tests.The desirability for this becomes clear when one considers the cost and timeinvolved in bioavailability studies as well as the safety issues involved in adminis-tering drugs to healthy subjects or patients. It would certainly be preferable to beable to substitute a quick, inexpensive in-vitro test for in-vivo bioavailability stud-ies. This would be possible if in-vitro tests could reliably and accurately predictdrug absorption and reflect the in-vivo performance of a drug in humans.

Disintegration Tests- The early attempts to establish an indicator of drug bioavailability focused on dis-integration as the most pertinent in-vitro parameter. The first official disintegra-tion test appeared in the United States Pharmacopeia (USP) in 1950. However,while it is true that a solid dosage form must disintegrate before significant disso-lution and absorption can occur, meeting the disintegration test requirement onlyinsures that the dosage form (tablet) will break up into sufficiently small particlesin a specified length of time. It does not ensure that the rate of solution of the drugis adequate to produce suitable blood levels of the active ingredient. Therefore,while the test for tablet disintegration is very useful for quality control purposes inmanufacturing, it is a poor index of bioavailability.

Dissolution Tests- Since a drug must go into solution before it can be absorbed, and since the rate atwhich a drug dissolves from a dosage form often determines its rate and/or extentof absorption, attention has been directed at the dissolution rate. It is currentlyconsidered to be the most sensitive in-vitro parameter most likely to correlate withbioavailability.

Official dissolution tests - There are two official USP dissolution methods: Apparatus 1, (basket method),and Apparatus 2 (paddle method). For details of these dissolution tests, the readeris recommended to consult USPXXII/NFXVII (66).

Dissolution tests are an extremely valuable tool in ensuring the quality of a drugproduct. Generally, product-to-product variations are due to formulation factors,such as particle size differences, excessive amounts of lubricant and coatings.These factors are reactive to dissolution testing. Thus, dissolution tests are veryeffective in discriminating between and within batches of drug product(s). Thedissolution test, in addition, can exclude definitively any unacceptable product.

Limitations of dissolution tests-

There are, however, problems with in-vitro dissolution testing which should benoted - problems which make correlation with in- vivo availability difficult. Thefirst is related to instrument variance and the absence of a standard method. Thetests described in the USP are but a few of the large number of dissolution methodsproposed to predict bioavailability. Since the dissolution rate of a dosage form isdependent on the methodology used in the dissolution test, changes in the appara-



tus, dissolution medium, etc., can dramatically modify the results. Table 8-9 onpage 17 lists some of the factors related to the dissolution testing device that canaffect the dissolution rate of the drug.

TABLE 8-9 Device factors affecting dissolution

Another significant problem is related to the difference between the in-vitro andin-vivo environments in which dissolution occurs. In-vitro studies are generallycarried out under controlled conditions in one, or perhaps two, standardized sol-vents. The in-vivo environment (the gastrointestinal tract), on the other hand, is acontinuously changing, complex environment. There are many variables whichcan affect the dissolution rate of a drug in the gastrointestinal tract, including pH,enzyme secretions, surface tension, motility, presence of other substances andabsorption surfaces (68). Thus, drugs frequently dissolve in the body at rates quitedifferent from those observed in an in-vitro test situation. Most of the official dis-solution tests tend to be acceleration dissolution tests which bear limited or norelationship with in-vivo dissolution.

Adding to the complexity of correlating dissolution with in-vivo absorption arefactors such as drug-drug interactions, age, food effects, health, genetic back-ground, biorhythm and physical activity (32, 69). All these factors may have aneffect on the rate and extent of absorption of a drug. Thus, the in-vivo environ-ment is far more complex, variable, and unpredictable than any in-vitro test envi-ronment, making in-vitro / in-vivo correlations very difficult. A simple dissolutiontest in a standardized vehicle cannot reflect the in vivo absorption of a drug across apopulation (70).

Parameters used- Proper selection of the in-vitro and in-vivo parameters to be correlated is criticalin achieving a meaningful correlation. The in-vitro parameter should be selectedthat has the greatest effect on the absorption characteristics of the drug (71). Thereare several approaches to establishing a correlation between the dissolution of a

1. Degree of agitation

2. Size and shape of container

3. Composition of dissolution medium

• pH

• ionic strength

• viscosity

• surface tension

4. Temperature of dissolution medium

5. Volume of dissolution medium

6. Evaporation

7. Hydrodynamics (flow pattern)

Source: Ref. 67



drug in in- vitro and the bioavailability of a drug in-vivo. The in-vitro - in-vivocorrelative methods used most often are of the single-point type where the dissolu-tion rate (expressed as the percent of drug dissolved in a given time, or the timerequired for a given percent of the drug to dissolve) is correlated to a certainparameter of the bioavailability. Examples of in-vivo parameters used includeCmax, AUC, time to reach half-maximal plasma concentration, the averageplasma concentration after 0.5 or 1 hour, maximum urinary excretion rate, andcumulative percent excreted in urine after a given time (71- 78). According toWagner, the best in-vitro variable to use is the time for 50 percent of the drug todissolve, and the best variable from in-vivo data to use is the time for 50 percent ofthe drug to be absorbed (79).

Ideally, one would hope to find a linear relationship between some measurement ofthe dissolution test and some measurement based on bioavailability studies.Unfortunately, most attempts to accomplish this objective have failed.

8.1.6 IN-VITRO / IN-VIVO CORRELATION STUDIES-

There have been many attempts to establish in-vitro / in-vivo correlations for alarge variety of drugs. Some of these studies have been summarized by Welling,Banakar, and Abdou (71, 80-82).

While there are many published examples of satisfactory correlations betweenabsorption parameters and in-vitro dissolution tests, most studies have resulted inpoor, or moderate, in-vitro - in-vivo correlations, often involving agreement withonly one of the critical bioavailability parameters. Moreover, the positive correla-tions that have been found generally apply only to the specific formulation studied.There have been instances where the dissolution rates or various formulations ofthe same drug have been significantly different, yet little or no difference wasobserved in their bioavailability parameters (83-85). There have also been caseswhere a drug has failed to meet compendia dissolution standards but has demon-strated adequate bioavailability (86). Welling states: "To the writer's knowledge,there have been no studies that have accurately correlated in- vitro and in-vivo datato the point that the use of upper and lower limits for in-vitro dissolution parame-ters can be confidently used to predict in-vivo behavior and, therefore, to replacein-vivo testing" (71).

Even if an in-vitro test could be designed that would accurately reflect the dissolu-tion process in the gastrointestinal tract, dissolution is only one of many factorsthat affect a drug's bioavailability. For example, saturable presystemic metabolismmay affect the extent of drug absorption, but this would not be predicted by an



in-vitro test. Dissolution studies also would not predict poor bioavailability due toinstability in gastric fluid or complexation with another drug or food component.

Thus, the ultimate evaluation a drug product's performance under the conditionsexpected in clinical therapy must be an in-vivo test; a dissolution test is unlikely toentirely replace bioavailability testing (70, 87, 88). In-vitro methods are importantin the development and optimization of dosage forms while in-vivo tests are essen-tial in obtaining information on the behavior of medication in living organisms.One cannot be substituted for the other (69).



8.2 Bioequivalence

Definitions With the phenomenal increase in the availability of generic drugs in recent years,the issues of bioavailability and bioequivalence have received increasing attention.In order for a drug product to be interchangeable with the pioneer (innovator orbrand name) product, it must be both pharmaceutically equivalent and bioequiva-lent to it. According to the FDA, "pharmaceutical equivalents" are drug productsthat contain identical active ingredients and are identical in strength or concentra-tion, dosage form, and route of administration (89). However, pharmaceuticalequivalents do not necessarily contain the same inactive ingredients; various man-ufacturers' dosage forms may differ in color, flavor, shape, and excipients. Theterms "pharmaceutical equivalents" and "chemical equivalents" are often usedinterchangeably.

"Bioequivalence" is a comparison of the bioavailability of two or more drug prod-ucts. Thus, two products or formulations containing the same active ingredient arebioequivalent if their rates and extents of absorption are the same. When a newformulation of an existing drug is developed, its bioavailability is generally evalu-ated relative to the standard formulation of the originator. Indeed, a bioequiva-lence trial against the standard formulation is the key feature of an AbbreviatedNew Drug Application (ANDA) submitted to the Food and Drug Administrationby a manufacturer who wishes to produce a generic drug. For a generic drug to beconsidered bioequivalent to a pioneer product, there must be no statistical differ-ences (as specified in the accepted criteria) between their plasma concentra-tion-time profiles. Because two products rarely exhibit absolutely identicalprofiles, some degree of difference must be considered acceptable, as will be dis-cussed later.

Since the concentration of a drug in blood is used as an assessment of its clinicalperformance, inherent in the demonstration that two preparations containingequivalent amounts of the same drug produce similar concentrations of the drugentity in blood is the assumption that they will elicit equivalent drug responses.Thus, two products that are deemed to be bioequivalent are also assumed to betherapeutically equivalent, and therefore interchangeable. This principle is funda-mental to the concept of bioequivalence and is the basic premise on which it isfounded.

In general, the FDA considers two products to be "therapeutic equivalents" if theyeach meet the following criteria (90):

1. they are pharmaceutical equivalents,

2. they are bioequivalent (demonstrated either by a bioavailability measurement or an in vitro stan-dard),



3. they are in compliance with compendial standards for strength, quality, purity and identity,

4. they are adequately labelled, and

5. they have been manufactured in compliance with Good Manufacturing Practices as established by the FDA.

Background The first intimations of bioequivalence problems with multi-source drug productswere given by early investigations of the availability of vitamins, aspirin, tetracy-cline, and tolbutamide (91-97). In 1974, after an extensive review of the bioavail-ability of drugs, Koch-Weser concluded that " . . . among drugs thus far testedbioinequivalence of different drug products has been far more common thanbioequivalence" (98). Of particular note were the studies involving digoxin; thefindings of these investigations sparked the discussion about bioequivalenceassessment that still continues today. Significant differences were seen in the bio-availability of digoxin not only between products supplied by different companies,but also between lots obtained from the same manufacturer (99). Because of thenarrow therapeutic range for this drug, and because the drug is utilized in the treat-ment of cardiac patients, these findings generated a great deal of concern.

Similar reports of bioinequivalence and therapeutic inequivalence appeared forother drugs as well, including phenytoin, phenylbutazone, chloramphenicol, tolb-utamide and thyroid (6). The clinical significance of these reported differences inbioavailability relates to the therapeutic index of the drug, the dose of the drug andthe nature of the disease. In 1973 the Ad Hoc Committee on Drug Product Selec-tion of the American Pharmaceutical Association published a list of drugs with apotential for therapeutic inequivalence based on reported evidence of bioinequiva-lence (100). The drugs fall in three categories: "high," "moderate," or "low risk"based on the clinical implications (Table 8-10 on page 22).



TABLE 8-10 Drugs with various risk potential for inequivalence

The concern about the bioinequivalence of some drugs led to the establishment in1974 of the Drug Bioequivalence Study Panel of the Office of Technology Assess-ment (OTA). The objective was to ensure that drug products of the same physicaland chemical composition would produce similar therapeutic effects. Among the11 recommendations of the Panel was the conclusion that not all chemical equiva-lents were interchangeable, but the goal of interchangeability was achievable formost oral drug products (101). The Report recommended that a system should beorganized as rapidly as possible to generate an official list of interchangeable drugproducts. The OTA Report, as well as the growing awareness within the scientificand regulatory communities of bioavailability problems with marketed drug prod-ucts, focused the attention of the FDA on bioequivalence and bioavailability prob-lems and issues.

High Risk Potential Moderate Risk Potential Low or Negligible Risk Potential

aminophylline

aspirin (when used in high dose levels)

bishydroxycoumarin

digoxin

dipheylhydantoin (phenytoin)

para-aminosalicylic acid

prednisolone

prednisone

quinidine

warfarin

amphetamines

(sustained-release)

ampicillin

chloramphenicol

chlorpromazine

digitoxin

erythromycin

griseofulvin

oxytetracycline

penicillin G (buffered)

pentobarbital

phenylbutazone

phenacetin

potassium chloride (solid dosage forms)

salicylamide

secobarbital

sulfadiazine

tetracycline

tolbutamide

acetaminophen

codeine

ferrous sulfate

hydrochlorothiazide

ephedrine

isoniazid

meprobamate

penicillin VK

sulfisoxazole



8.2.1 BIOEQUIVALENCE REGULATIONS

In 1977, the FDA implemented a series of bioavailability and bioequivalence regu-lations which formed the basis of subsequent discussion, if not controversy, oftherapeutic equivalency of drug products (102). The regulations are divided intotwo separate regulations; Subpart B - Procedures for Determining the Bioavail-ability of Drug Products and Subpart C - Bioequivalence Requirements. WhileTable 11 summarizes the key provisions of the bioavailability regulations, thosefor bioequivalence requirements are summarized in Table 8-11 on page 23.

TABLE 8-11 Key provisions for bioavailabilty regulations

Criteria for establishing a bioequivalence requirement -

The 1977 Bioequivalence regulations set forth the following criteria and evidencesupporting the establishment of a bioequivalence requirement for a given drugproduct:

1. Evidence from well-controlled clinical trials or controlled observations in patients that such products do not give comparable therapeutic effects.

2. Evidence from well-controlled bioequivalence studies that such products are not bioequivalent drug products.

3. Evidence that the drug products exhibit a narrow therapeutic ratio, (e.g., there is less than a two-fold difference in the median lethal dose (LD50) and median effective dose (ED50) value or have less than a two-fold difference in the minimum toxic concentration and minimum effec-tive concentrations in the blood), and safe and effective use of the drug product requires careful dosage titration and patient monitoring.

4. Competent medical determination that a lack of bioequivalence would have a serious adverse effect in the treatment or prevention of a serious disease or condition.

5. Physicochemical evidence of any of the following:

a. The active drug ingredient has a low solubility in water--e.g., less than 5 mg/ml.

b. The dissolution rate of one or more such products is slow--e.g., less than 50 percent in thirty minutes when tested with a general method specified by an official compendium or the FDA.

c. The particle size and/or surface area of the active drug ingredient is critical in determining bioavailability.

1. Defines bioavailability in terms of both the rate and extent of drug absorption.

2. Describes procedures for determining the bioavailability of drug products.

3. Sets forth requirements for submission of in vivo bioavailability data.

4. Sets forth criteria for waiver of human in vivo bioavailability studies.

5. Provides general guidelines for the conduct of in vivo bioavailability studies.

6. Imposes a requirement for filing an Investigational New Drug Application.

Source: Ref. 103



d. Polymorphs, solvates, complexes, and such, exist that could contribute to poor dissolution and may affect absorption.

e. There is a high excipient/active drug ratio present in the drug product--e.g., greater than 5 to 1.

f. The presence of specific inactive ingredients (e.g. hydrophilic or hydrophobic excipients) that either may be required for absorption of the active drug or may interfere with such absorp-tion.

6. Pharmacokinetic evidence of any of the following:

a. The drug is absorbed in large part in a particular segment of the gastrointestinal tract or is absorbed from a localized site.

b. Poor absorption of the drug, even when it is administered as a solution--e.g., less than 50 percent compared to an intravenous dose.

c. The drug undergoes first-pass metabolism in the intestinal wall or liver.

d. The drug is rapidly metabolized or excreted, requiring rapid dissolution and absorption for effectiveness.

e. The drug is unstable in specific portions of the gastrointestinal tract, requiring special coatings and formulations--e.g., enteric coatings, buffers, film coatings--to ensure adequate absorption.

f. The drug follows nonlinear kinetics in or near the therapeutic range, and the rate and extent of absorption are both important to bioequivalence.

Types of Bioequivalence Requirements

In the event that a drug meets one or more of the above six criteria, a bioequiva-lence requirement is established. The requirement could be either an in-vivo or anin-vitro investigation, as specified by the FDA. The types of bioequivalencerequirements include the following:

1. An in-vivo test in humans.

2. An in-vivo test in animals that has been correlated with human in- vivo data.

3. An in-vivo test in animals that has not been correlated with human in- vivo data.

4. An in-vitro bioequivalence standard, i.e., an in-vitro test that has been correlated with human in-vivo bioavailability data.

5. A currently available in-vitro test (usually a dissolution rate test) that has not been correlated with human in-vivo bioavailability data.

The regulations state that in-vivo testing in humans would generally be required ifthere is well-documented evidence that pharmaceutical equivalents intended to beused interchangeably meet one of the first three criteria used to establish abioequivalence requirement:

1. The drug products do not give comparable therapeutic effects.

2. The drug products are not bioequivalent.

3. The drug products exhibit a narrow therapeutic ratio (as described above), and safe and effec-tive use of the product requires careful dosage titration and patient monitoring.



Criteria for waiver of evidence of in-vivo bioavailability -

Although a human in-vivo test is considered to be preferable to other approachesfor the most accurate determination of bioequivalence, there is a provision in the1977 regulations for waiver of an in-vivo bioequivalence study under certain cir-cumstances. For some drug products, the in-vivo bioavailability of the drug maybe self-evident or unimportant to the achievement of the product's intended pur-poses. The FDA will waive the requirement for submission of in-vivo evidence ofbioavailability or bioequivalence if the drug product meets one of the followingcriteria:

1. The drug product is a solution intended solely for intravenous administration, and contains the active drug ingredient in the same solvent and concentration as an intravenous solution that is the subject of an approved full New Drug Application (NDA).

2. The drug product is a topically applied preparation intended for local therapeutic effect.

3. The drug product is an oral dosage form that is not intended to be absorbed, e.g., an antacid.

4. The drug product is administered by inhalation and contains the active drug ingredient in the same dosage form as a drug product that is the subject of an approved full NDA.

5. The drug product is an oral solution, elixir, syrup, tincture or other similar soluble form, that contains an active drug ingredient in the same concentration as a drug product that is the subject of an approved full NDA and contains no inactive ingredient that is known to significantly affect absorption of the active drug ingredient.

6. The drug product is a solid oral dosage form (other than enteric-coated or controlled-release) that has been determined to be effective for at least one indication in a Drug Efficacy Study Implementation (DESI) notice and is not included in the FDA list of drugs for which in vivo bioequivalence testing is required.

7. The drug product is a parenteral drug product that is determined to be effective for at least one indication in a DESI notice and shown to be identical in both active and inactive ingredients for-mulation, with a drug product that is currently approved in an NDA. (Excluded from the waiver provision are parenteral suspensions and sodium phenytoin powder for injection.)

According to the regulations, the bioavailability of certain drug products may bedemonstrated by evidence obtained in-vitro in lieu of in-vivo data. Thus, the FDAalso permits waiver of the in-vivo requirements if a drug product meets one of thefollowing criteria:

1. The drug product is one for which only an in-vitro bioequivalence requirement has been approved by the FDA.

2. The drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to another drug product made by the same manufac-turer and the following conditions are met:

a. the bioavailability of this other product has been demonstrated

b. both drug products meet an appropriate in-vitro test approved by the FDA

c. the applicant submits evidence showing that both drug products are proportionally similar in their active an inactive ingredients.

3. The drug product is shown to meet an in-vitro test that assures bioavailability, i.e., an in-vitro test that has been correlated with in-vivo data.



4. The drug product is a reformulated product that is identical, except for color, flavor, or preserva-tive, to another drug product made by the same manufacturer, and both of the following condi-tions are met:

a. the bioavailability of the other product has been demonstrated.

b. both drug products meet an appropriate in vitro test approved by the FDA.

5. The drug product contains the same active ingredient and is in the same strength and dosage form as a drug product that is the subject of an approved full NDA or Abbreviated New Drug Application (ANDA) and both drug products meet an appropriate in-vitro test that has been approved by the FDA.

Although the above list of criteria for waiver of an in-vivo bioavailability study isquite lengthy, currently virtually all new tablet or capsule formulations from whichmeasurable amounts of drug or metabolites are absorbed into the systemic circula-tion require a human bioequivalence study for approval (104).

TABLE 8-12 Key Provisions for bioequivalence requirements

8.2.2 STUDY DESIGN

A single-dose bioequivalency study is generally performed in normal, healthy,adult volunteers. The subject population should be selected carefully, so that prod-uct formulations, and not intersubject variations, will be the only significant deter-minants of bioequivalence (105). A minimum of 12 subjects is recommended,although 18 to 24 subjects are used to increase the data base for statistical analysis.The test and the reference products are usually administered to the subjects in thefasting state (overnight fast for at least 10 hours, plus 2 to 4 hours after administra-tion of the dose), unless some other approach is more appropriate for valid scien-tific reasons. These subjects should not take any other medication for one weekprior to the study or during the study. The bioavailability is determined by the col-lection of either blood samples or urine samples over a period of time and mea-surement of the concentration of drug present in the samples.

Generally, a crossover study design is used. Using this method, both the test andthe reference products are compared in each subject, so that inter-subject variables,

1. Defines procedures for establishing a bioequivalence requirement.

2. Sets forth criteria to establish a bioequivalence requirement.

3. Describes types of bioequivalence requirements.

4. Sets forth requirement for in-vitro batch testing and certification.

5. Describes requirements for marketing a drug product subject to a bioequivalence requirement.

6. Sets forth requirements for in-vivo testing of a drug product not meeting an in-vitro bioequiv-alence standard.

Source: Ref. 103



such as age, weight, differences in metabolism, etc., are minimized. Each subjectthus acts as his own control. Also, with this design, subjects' daily variations aredistributed equally among all dosage forms or drug products being tested.

The subjects are randomly selected for each group and the sequence of drugadministration is randomly assigned. The administration of each product is fol-lowed by a sufficiently long period of time to ensure complete elimination of thedrug (washout period) before the next administration. The washout period shouldbe a minimum of 10 half-lives of the administered drug (106). A waiting period ofone week between administration is usually an adequate washout period of mostdrugs.

With a drug requiring a washout period of one week, a typical randomized two-way crossover bioequivalency study is shown in Table 8-13 on page 27.

TABLE 8-13 Two way cross over design

a 10 subjects per group

Assuming that the in-vivo performances of the two formulations are to be com-pared by examining their blood level profiles, one must be certain that an adequatenumber of blood samples are taken. Blood samples should be drawn with suffi-cient frequency to provide an accurate characterization of the drug concentra-tion-time profile from which tmax, Cmax and AUC can be determined. Typically,a total of 10 to 15 sampling times might be required (107). Moreover, all samplesshould be taken at the same time for both the test and the reference product to per-mit proper statistical analysis.

Additional features which contribute to good study design include:

1. All drug samples obtained for the test and reference preparations should be analyzed by the same method.

2. Identical test conditions must be used for the two groups of subjects. For example, the types of foods, fluid intake, physical activity, and posture should all be rigidly controlled in the study.

3. The physical characteristics of the subjects (such as age, height, weight, and health) should be standardized.

Treatment

Groupa Week 1 Week 2

I II

A B

B A



Several important questions have been raised specifically regarding the design ofthe bioequivalence tests. One of these deals with the selection of the appropriatereference standard, since this is a critical component of a protocol (6, 108). Nor-mally, the reference product is that available from the innovator company holdingthe New Drug Application. However, in cases where there may be some questionas to the bioavailability of such a product, the study may utilize a solution of thedrug instead of or in addition to the marketed product. The use of a solution can,of course, result in some difficulty in interpretation of the data: a solid dosageform, when compared to a solution, will usually exhibit a lower Cmax and a longertmax. The clinical significance of these differences may be difficult to assess.

In some instances, the FDA must designate a specific product as the referencestandard from among two or more possible products; e.g., Proventil® tablets, 4 mg(Schering), not Ventolin® tablets 4 mg (Allen and Hanburys), is the referenceproduct in bioequivalence studies of albuterol sulfate conventional tablets (108).

Advantages of Multiple-dose vs. single dose studies:

Another important question is whether the bioequivalence trial should comparesingle doses of the formulations or if it should compare "steady-state" conditionsreached after multiple dosing. It would seem that multiple dosing would be thelogical choice for drugs intended for long-term use since this would give a morerealistic comparison in view of the way in which the drug is normally adminis-tered. Other advantages of conducting a multiple-dose study over a single-dosestudy include (54, 59):

1. Multiple-dosing eliminates the long washout periods required between single-dose administra-tions. The switch-over from one formulation to the other can take place in steady state.

2. Single-dose studies may pose problems of sufficiently long sampling periods in order to get reli-able estimates of terminal half-life, which is needed for correct calculation of the total AUC.

3. Multiple-dose studies yield higher concentrations of drug in the blood, making accurate mea-surement easier. In addition, since drug concentrations need to be measured only over a single dosing interval at steady state, the need to measure lower concentrations during a disposition phase is avoided.

4. Multiple-dosing studies can be conducted in patients, rather than healthy volunteers, allowing the use of higher doses.

5. Usually, smaller intersubject variability is observed in steady-state studies, which may permit the use of fewer subjects.

6. Nonlinear pharmacokinetics, if present, can be more readily detected at steady-state following multiple-dosing.

Thus, for some drug products, multiple-dose bioequivalence studies are appropri-ate and should be performed. In fact, according to one of the conclusions of theBio- International '92 conference on the bioequivalence of highly variable drugs, amultiple-dose study is required in the case of compounds exhibiting nonlinearpharmacokinetics (110). The circumstances under which a multiple-dose studymay be required are summarized in the regulations (109):



1. When there is a difference in the rate of absorption but not in the extent of absorption.

2. When there is excessive variability in bioavailability from subject to subject.

3. When the concentration of the active moiety in the blood resulting from a single dose is too low for accurate determination.

4. When the drug product is a controlled-release dosage form.

On the other hand, multiple-dose bioequivalence studies are undesirable in somerespects. Healthy subjects should not be dosed with any drug for an extendedperiod of time (59). Multiple-dose studies are also generally more difficult tocarry out, especially with regard to ensuring subject compliance with dosing anddietary restrictions. Therefore, most bioequivalence studies are conducted as sin-gle-dose studies. Multiple-dose studies should be performed only when a sin-gle-dose study is not a reliable indicator of bioavailability (111).

8.2.3 ASSESSMENT OF BIOEQUIVALENCE

In order for different formulations of the same drug substance to be consideredbioequivalent, they must be equivalent with respect to the rate and extent of drugabsorption. Thus, the two predominant issues involved in the assessment ofbioequivalence are: the pharmacokinetic parameters that best characterize the rateand extent of absorption and, the most appropriate method of statistical analysis ofthe data.

Pharmacokinetic criteria With regard to the choice of the appropriate pharmacokinetic characteristics,Westlake suggests comparisons of the formulations should be made with respect toonly those parameter(s) of the blood level profile that possess some meaningfulrelation to the therapeutic effect of the drug (107). Since the AUC is directly pro-portional to the amount of drug absorbed, this pharmacokinetic parameter is mostcommonly used to characterize the extent of absorption, both in single- and multi-ple- dose studies.

The choice of an appropriate pharmacokinetic characteristic for the rate of absorp-tion is still being discussed with considerable controversy (112, 113). Although abroad array of methods exists for calculating absorption rates (e.g. moment analy-sis, deconvolution procedures and curve-fitting), the most commonly used param-eters are peak concentration (Cmax) and time to peak concentration (tmax).Although these parameters have been observed to have significant variances andmay be difficult to determine accurately, they remain the parameters generallyrequested as rate characteristic by most regulatory authorities for immedi-ate-release products (112).

Statistical criteria After a bioequivalence study is conducted and the appropriate parameters aredetermined, the pharmacokinetic data must be examined according to a set of pre-determined criteria to confirm or refute the bioequivalency of the test and refer-



ence formulations. That is, one must determine whether the test and referenceproducts differ within a predefined level of statistical significance. Since the sta-tistical outcome of a bioequivalence study is the primary basis of the decision foror against therapeutic equivalence of two products, it is critically important that theexperimental data be analyzed by an appropriate statistical test.

In the early 1970s, bioequivalence was usually determined only on the basis ofmean data. Mean AUC and Cmax values for the generic product had to be within+20% of those of the reference (innovator) product (108). Although the 20% valuewas somewhat arbitrary, it was felt that for most drugs, a 20% change in the dosewould not result in significant differences in the clinical response to drugs (114).A relatively common misconception is that current regulatory standards still allowthis difference of 20% in the means of the pharmacokinetic variables (Cmax andAUC) of the test and reference formulations. The FDA's statistical criteria forapproval of generic drugs now requires the application of confidence limits to themean data, using an analysis known as the two one-sided tests procedure (115).This change came about as a result of the conclusion of the FDA BioequivalenceTask Force in 1986 that the use of a 90% confidence interval based on the twoone-sided t-tests approach was the best available method for evaluating bioequiva-lence (111).

Westlake was the first to suggest the use of confidence intervals as a means of test-ing for bioequivalence (116). Recognizing that no two products will result in iden-tical blood-level profiles, and that there will be differences in mean values betweenproducts, Westlake pointed out that the critical issue was to determine how largethose differences could be before doubts as to therapeutic equivalence arose (107,117). A test formulation was considered to be bioequivalent to a reference formu-

lation if and . (119). By this proce-

dure, if test and reference products were not bioequivalent (i.e. means differed bymore than 20%), there was a 5% chance of concluding that they are bioequivalent.

The current FDA guidelines are that two formulations whose rate and extent ofabsorption differ by -20%/+25% or less are generally considered bioequivalent(90). In order to verify that the -20%/+25% rule is satisfied, the two one-sided sta-tistical tests are carried out: one test verifies that the bioavailability of the testproduct is not too low and the other to show that it is not too high. The currentpractice is to carry out the two one-sided tests at the 0.05 level of significance.

Computationally, the two one-sided tests are carried out by computing a 90% con-fidence interval. For approval of an ANDA, a generic manufacturer must showthat the 90% confidence interval for the ratio of the mean response (usually AUC

0.8AUCtest

AUCref

------------------- 1.2< < 0.8Cpmax test

Cpmaxref

-------------------- 1.2< <



and Cmax) of its product to that of the innovator is within the limits of 0.8 to 1.25.Since these tests are carried out at the 0.05 level of significance, there is no morethan a 5% chance that they will be approved as equivalent if they differ by as muchor more than is allowed by the equivalence criteria (-20%/+25%).

Since this test requires that the 90% confidence interval of the difference betweenthe means be within a range of -20%/+25%, it is more stringent than simply requir-ing the comparison of the test and reference products' AUC and Cmax to be withinthe 80 to 125% range. If the mean response of the generic product in the studypopulation is near 20% below or 25% above the innovator mean, one or both of theconfidence limits will fall outside the acceptable range and the product will fail thebioequivalence test. Thus, the confidence interval requirement ensures that thedifference in mean values for AUC and Cmax will actually be less than -20%/+25%. It should be pointed out that the standards vary among drugs and drugclasses. For example, antipsychotic agents may fall within a 30% variation andantiarrhythmic agents may be allowed a 25% variation (122).

The actual differences between brand and generic products observed in bioequiva-lence studies have been reported to be small. The FDA has stated that forpost-1962 drugs approved over a two-year period under the Waxman-Hatch bill(1984), the mean bioavailability difference between the generic and pioneer prod-ucts has been about 3.5% (120). In addition, 80% of the generic drugs approvedby the FDA between 1984 and 1986 differed from the innovator products by anobserved difference of only +5%. Such differences are small when compared toother variables of drug therapy and would not be expected to produce clinicallyobservable differences in patient response.

8.2.4 CONTROVERSIES AND CONCERNS IN BIOEQUIVALENCE

The design, performance and evaluation of bioequivalence studies have received agreat deal of attention over the past decade from academia, the pharmaceuticalindustry and regulatory agencies. A number of concerns and questions have beenraised about the conduct of bioequivalence studies as well as the guidelines andcriteria used to determine bioequivalence (112). Many of these concerns were trig-gered by the passage of the Drug Price Competition and Patent Term RestorationAct (The Waxman-Hatch Amendments) by Congress in 1984. This Act providedfor an expedited approval by the FDA of generic drugs, thereby expanding thepotential generic market for prescription generic drugs (121). Shortly after thepassage of this Act, numerous published reports appeared in the scientific litera-ture questioning the FDA's ability to ensure that generic drugs were equivalent tothe brand name drugs they were copying. Most of the concerns of the scientificcommunity centered around adequate standards for evaluation of bioequivalence



and correlation between bioequivalence and therapeutic equivalence. Some of theissues and concerns that were raised are summarized in Table 8-14 on page 32 (8,13).

TABLE 8-14 Issues and Concerns regarding bioequivalence

At the center of the controversy were the methods and criteria used by the FDA todetermine bioequivalence. Assessment of bioequivalence was done on the basis ofmean data: mean AUC and Cmax values for the generic product had to be within+20% of those of the innovator product for approval. A statistical test wasemployed to assess the power of the test to detect a 20% mean difference in treat-ments. For drugs that could not meet the statistical criteria because of inherentvariability, another rule was used, the so-called "75/75" rule: that in at least 75%of the subjects, the test formulation must fall within the range of 75% to 125% ofthe reference standard to be considered equivalent (122). It was felt by many thatthese rules permitted too much variability in the bioavailability of test drugs andcould result in therapeutic failure or increased risk of side effects (4, 15, 123).

Statistically, the power approach and the 75/75 rule were shown to have poor per-formance characteristics and bioequivalence evaluation based on these methodswas discontinued by the FDA in 1986. In their place, the Agency currentlyemploys the two one-sided tests procedure, as previously discussed.

Although the decision of bioequivalence is now made in a more statistically validway and the associated concerns have diminished somewhat, some importantquestions and controversies in bioequivalence remain. These are primarily cen-tered around study design, the criteria used to establish or refute equivalence, andthe assumption that products that are bioequivalent are therapeutically equivalent.

One criticism of bioequivalence testing is that it is almost always done in a panelof young, healthy male volunteers rather than in the target population for which thedrug is intended. Clearly, the performance of a drug product in a 20-year-old malewill not be the same as in an 85-year-old woman. Serious concerns have been

• Correct analysis of drugs in biological fluids • Appropriate choice of pharmacokinetic parameters to assess bioequivalence • Generalizing results obtained in healthy volunteers to patients • Problems involved in extrapolating from single-dose studies to steady-state • Importance of evaluating active metabolites • Inadequate statistical criteria to evaluate bioequivalency • Bioequivalence does not always ensure therapeutic equivalence • Lack of clear guidelines for evaluation of bioequivalence



raised that different results would be observed in elderly patients, in women, inpatients with diseases of the gastrointestinal tract, and in patients with diminishedrenal or hepatic function. However, although factors such as age and disease statemight affect the actual observed concentrations of drug, the products being com-pared should be affected in a similar fashion, and one can still be compared to theother. If two products show an equivalent level in healthy volunteers, their levelsshould be elevated to the same extent in patients with impaired hepatic function.Thus, they can still be compared to each other. Healthy male volunteers are gener-ally used in bioequivalence studies to assure a homogeneous study population andto permit focus on formulation factors that might affect bioavailability. In addi-tion, healthy subjects are more likely to remain stable during the study. The condi-tion of actual patients might change due to the disease resulting in greatervariability in the data. The FDA does recognize the possibility that some condi-tions could cause two products that are bioequivalent in healthy subjects to be bio-inequivalent in certain patients and is prepared to modify its guidelines ifnecessary.

A study design-related area of concern is average versus individual bioavailability.Current procedures assess equivalence in terms of average bioavailabilities, and donot address within-subject equivalence. In recent years, there has been increasedinterest expressed in the variability of response, particularly variability within anindividual. This has given rise to the most recent controversy in bioequivalenceassessment, namely whether average bioequivalence is adequate to allow inter-changeability of drugs in an individual (112). Anderson and Hauck believe that adifferent, more stringent, notion of bioequivalence, referred to as individualbioequivalence, is needed to provide assurance that an individual patient can beswitched from one formulation to another (124).

The second major area of controversy has focused on the criteria used to determinebioequivalence. Implicit in the FDA guidelines is the assumption that a -20%/+25% change in mean serum concentration of drugs can be safely tolerated. How-ever, there is little documentation demonstrating whether 20% variation in bio-availabilities does or does not affect the safety and efficacy of drugs. There arecertain critical therapeutic categories (Table 8-15 on page 34) in which minor fluc-tuations in blood levels may have a substantial impact on therapeutic outcome ortoxicity (125, 126). In view of this, some scientists believe that the FDA should bemore stringent, requiring the mean values for AUC to be within 10% rather than20%/25%. The Bioequivalence Task Force, in its 1988 report, concluded that forcertain drugs or drug classes, there is clinical evidence that may indicate a need fortighter limits than the then-generally applied +20% rule (111). The Task Forcerecommended that the Agency consider using as an "additional nonstatistical crite-rion" a mean difference in AUC of +10%; however, this additional criterion wouldnot be essential to ensuring drug bioequivalence.



TABLE 8-15 Critical Therapeutic Catagories of Drugs

In general, the choice of the appropriate bioequivalence range should be done onclinical grounds; for a drug with a narrow therapeutic range, more stringent limitsshould be considered. On the other hand, the current requirements for Cmax forsome drugs may be too stringent, considering the difficulty in accurately estimat-ing this value. For example, it has been suggested that the acceptable bioequiva-lence range for Cmax for fast-releasing nifedipine formulations should be 70% to130%, rather than the usual 80% to 125%. In light of this, many, including thePharmaceutical Research and Manufacturers of America (formerly the Pharmaceu-tical Manufacturers Association [PMA]), feel that the FDA should repudiate its-20%/+25% rule and develop drug-by- drug bioequivalence criteria (127).

A third source of controversy in bioequivalence is the very foundation on whichthe whole concept of bioequivalence is based: the central assumption is that if twoproducts are shown to be bioequivalent by currently accepted standards, then theyare also therapeutically equivalent, and thus interchangeable. A number of criticshave challenged this "bioequivalence = therapeutic equivalence" equation, point-ing out that this relationship has not been conclusively established for most drugs(9, 13, 16, 128). These terms are, in fact, not interchangeable; bioequivalencemeans that two products have basically superimposable blood level curves (withinspecified limits) while therapeutic equivalence means the products produce similareffects. There may be situations where two products have similar blood concentra-tions, yet if the drug has a narrow therapeutic range, they may have significantlydifferent therapeutic effects. On the other hand, there may be products which havewidely varying blood level profiles, but exhibit very little difference in their clini-cal effect. This might be the case for drugs with a wide therapeutic range. In addi-tion, the therapeutic efficacy of some drugs is not necessarily related to their bloodlevels, e.g., some psychoactive drugs, where the end point of drug effects is psy-chological and behavioral response (129).

Category Example

Cardiovascular drugs

Anticonvulsants

Bronchodilating agents

Oral anticoagulants

digoxin

phenytoin

theophylline

warfarin



Williams suggests several ways that the integrity of a bioequivalence study as aprediction of therapeutic equivalence could be assessed (104). One way involvesthe performance of specific clinical studies to confirm that products shown to bebioequivalent in healthy subjects would be bioequivalent in the patient populationas well. A second way suggested is through post-marketing surveillance of thera-peutic response produced by different formulations of the same drug under actualconditions of use. A third method is based on anecdotal reports. Williams pointsout that none of these methods have been systematically employed to confirm cur-rent bioequivalence methodology.

Thus, a number of problems remain in the bioequivalence process which should beaddressed. FDA scientists themselves have readily acknowledged the existence ofshortcomings in the bioequivalence testing program. However, a great deal ofprogress has been made in this area in the last twenty years. The improved designof the studies, the interpretation of the data, the increased scientific rigor of theacceptance criteria, as well as the more rigorous auditing and inspection programhave made bioequivalence data an appropriate and valid means of approvinggeneric drug products.

8.2.5 GENERIC DRUGS AND PRODUCT SELECTION

Generic drug utilization has increased dramatically in the last 20 years. In 1975,approximately 9% of all prescription drugs dispensed were generic versions (130).This percentage rose to 20% in 1984, and 40% in 1991. It has been variously esti-mated that the generic share of all new prescriptions will be 46% to 65% in 1995(131-133).

This rise of generics has not gone altogether smoothly, however; the popularity ofgeneric drugs took a sharp downturn in 1989 when scandal rocked the generic drugindustry. This involved illegal and unethical acts by some generic drug companies-- payoffs to FDA employees and fraudulent drug-approval test -- aimed at gettingdrugs approved ahead of other firms (134-138).

Although these events did shake the confidence of pharmacists, physicians and thepublic in the quality of generic drugs and cast a shadow over generics generally,these concerns were relatively short-lived. Numerous surveys conducted one totwo years after the scandal unfolded indicated that confidence in generic drugs hadbeen regained and that the generic industry was in better shape with pharmaciststhan it had been before the scandal occurred (139-146). Given the seriousness ofthe events, the speed with which generics came back was impressive. This wasdue in part to the FDA's reaction to the scandal: a multilevel reorganization of itsgeneric drug operations and a comprehensive inspection of the leading manufac-



turers of generic drugs (134, 140, 147, 148). It was felt that this stringent FDAreview of generics proved the overall integrity of the companies that emerged witha clean bill of health. After a sharp drop in the use of generic drugs in 1989, theybegan to rise nearly as quickly as they fell, and by mid-1990, sales of genericswere approaching their previous record high (141).

This trend in generic drug utilization is expected to continue its upward spiral, withnewly generic drugs coming to market at an increasing rate. There are several fac-tors that have contributed to this period of considerable growth in the generic drugindustry. One major factor was the passage of the Drug Price Competition andPatent Term Restoration Act (Waxman-Hatch Act) in 1984. This act, by eliminat-ing the requirement for clinical safety and efficacy testing for generics of drugsintroduced after 1962, greatly expedited the entry of generic drugs into the market-place. The purpose of this act was to facilitate generic competition and therebyreduce health care costs. This act significantly expanded the number of drugs eli-gible to be manufactured as generics. Another factor fueling the surge of genericproducts is the abundance of brand name drugs whose patents began expiring in1986. Between 1991 and 1994, patents expired on brand-name drugs whose com-bined annual sales totaled $10 billion (141). These include Procardia®, Ceclor®,Tagamet®, Cardizem®, Feldene®, Naprosyn®, and Xanax®. All told, more than100 drugs worth upwards of $25 billion in sales will have come off patent by theyear 2000 (149). Table 8-16 on page 37 lists some recent and impending patentexpirations (150, 151). As a result of these patent expirations on popular drugs,there has been an explosion of new generic drug applications.



TABLE 8-16 Recent and pending patent expirations

*Extentions may be granted

Perhaps the major factor promoting generic drug utilization is the increased atten-tion to containing health-care costs. Pushed by a drive for lower-cost medicationby federal and state governments, private insurers, corporate benefit managers,regulatory agencies and consumer groups, generic drug usage is at a peak. Addi-tional impetus could come from health care reform, wherein generic drugs areviewed as a key to controlling pharmaceutical costs. Managed care programs areexpected to cover more than 70% of all outpatient prescriptions by the end of thedecade, with an accompanying greater demand for generic products (152). Thusthe demand for generic drugs will continue to rise, in a climate that favors healthcare reform, lower- cost medications and broad-based prescription benefits (153).

With the increasing availability of generic drugs, pharmacists are called upon moreand more often to select a patient's drug product from a myriad of multisourceproducts. The pharmacist's role in product selection has increased dramatically inthe past decade and the proper selection of multisource drug products has becomea major professional responsibility of pharmacists. Although most pharmacists donot, realistically, evaluate the bioequivalence of two products from blood leveldata, professional judgement does need to be exercised; and this requires an under-standing and application of the biopharmaceutical principles discussed.

Brand Name Generic Name Patent Expiration Date*

ProcardiaTenorminCeclorCardizemFeldeneNaprosynXanaxTagametSeldaneMicronaseCapotenZantacTrentalNoroxin

NifedipineAtenololCefaclorDiltiazemPiroxicamNaproxenAlprazolamCimetidineTerfenadineGlyburideCaptoprilRanitidinePentoxifyllineNorfloxacin

19911991199219921992199319931994199419941995199519971998



8.2.6 THE ORANGE BOOK

One of the factors that led to the widespread repeal of the state anti-substitutionlaws in the 1970's was an effort by the states to contain drug costs and the estab-lishment of maximum allowable costs (MACs) for reimbursement of drugs underMedicaid. By allowing the pharmacist to select the manufacturer of a drug, theless- expensive generic version could be dispensed. However, before the pharma-cist could knowledgeably select a generic drug, he had to know which genericswere bioequivalent to the innovator product and thus, interchangeable. (There wassubstantial evidence at this time that not all pharmaceutically equivalent productswere bioequivalent). To answer this need, the states began preparing either posi-tive or negative formularies, often turning to the FDA for assistance in this under-taking.

In response to the many requests for assistance from the states in developing theirformularies, the FDA Commissioner notified state officials of FDA's intent to pro-vide a list of all prescription drug products that have been approved as being safeand effective, along with therapeutic equivalence determinations for multisourceprescription products. This list, entitled Approved Drug Products with Therapeu-tic Equivalence Evaluations, more commonly known as "The Orange Book" wasfirst published in 1980 and is now in its 14th edition. It is published annually andupdated monthly. The Orange book is generally considered to be the most reliableguide for determining which drug products are therapeutically equivalent.

The Prescription Drug Products List contains:

1. all the drug products approved by the FDA as being safe and effective under the Federal Food, Drug and Cosmetic Act, and

2. 2.the therapeutic equivalence evaluations for all approved multisource prescription drug prod-ucts (those pharmaceutical equivalents available from more than one manufacturer).

Currently, multisource products comprise almost 80% of the approximately 10,000drugs on the Prescription Drug Product List. The therapeutic evaluation for theseproducts have been prepared to serve as information and advice to state healthagencies, pharmacists and prescribers to promote knowledgeable drug productselection and to foster containment of health costs.

8.2.7 THERAPEUTIC EQUIVALENCE

Drug products are considered to be therapeutic equivalents if they are pharmaceu-tical equivalents and if they can be expected to have the same clinical effect whenadministered to patients as specified in the labeling (90). In general, the FDA



evaluates as therapeutically equivalent those drug products that satisfy the follow-ing general criteria:

1. They are approved as safe and effective.

2. They are pharmaceutical equivalents; i.e. they

a. contain identical amounts of the same active ingredient in the same dosage form and route of administration, and

b. meet compendial and other applicable standards for quality, purity, strength and identity.

3. They are bioequivalent. Bioequivalence may be established by either an in-vivo or in-vitro test, depending on the drug. If the drug presents a known or potential bioequivalence problem then an appropriate standard must be met which demonstrates a comparable rate and extent of absorption.

4. They are adequately labeled.

5. They are manufactured in compliance with Current Good Manufacturing Practice regulations.

The FDA believes that drug products meeting the above criteria are therapeuticallyequivalent and can be substituted with the full expectation that the substitutedproduct will produce the same therapeutic effect as the prescribed product.

8.2.8 THERAPEUTIC EQUIVALENCE EVALUATION CODES-

The FDA uses a two-letter coding system for multisource products. The first letterin the code allows users to determine whether a particular product has been evalu-ated therapeutically equivalent to other pharmaceutically equivalent products. Thesecond letter in the code provides additional information about the basis of FDA'sevaluation. The various categories are summarized in Table 8-17 on page 40.



TABLE 8-17 Therapuetic equivalency codes

"A" Drug Products "B" Drug Products

Drug products the FDA considers to be therapeutically equivalent; i.e. drug

products for which:

1. There are no actual or potential bioequivalence problems. These are

designated as:

AA Products in conventional dosage forms

AN Solutions and powders for aerosolization

AO Injectable oil solutions

AP Injectable aqueous solutions

AT Topical products

2. Actual or potential bioequivalence problems have been resolved via

adequate in vivo and/or in vitro tests. These are designated as AB.

Drug products the FDA does not consider to be therapeutically equivalent; i.e.

drug products for which actual or potential bioequivalence problems have not

been resolved by adequate evidence of bioequivalence. Often the problem is

with specific dosage forms rather than with the active ingredient. These products

are classified as "B" for one of three reasons:

1. The active ingredients or dosage forms have documented or potential bioequivalence problems, and no adequate studies demonstrating bioequivalence have been submitted.

2. The quality standards are inadequate or the FDA has insufficient

basis to determine therapeutic equivalence.

3. The drug product is under regulatory review.

These products are designated as:

BC Controlled-release tablets, capsules and injectables

BD Active ingredients and dosage forms with documented bioequivalence problems

BE Delayed-release oral dosage forms (e.g. enteric-coated products)

BN Products in aerosol-nebulizer drug delivery systems

BP Active ingredients and dosage forms with potential bioequiva-lence problems

BR Suppositories or enemas that deliver drugs for systemic absorption

BS Products having drug standard deficiencies

BT Topical products with bioequivalence issues

BX Insufficient data to determine therapeutic equivalence

B* Drug products requiring further FDA investigation and review to determine equivalence



There are two basic categories into which multisource drugs have been placed, "A"or "B". Drug products rated "A" are products that the FDA considers to be thera-peutically equivalent to the pharmaceutically equivalent original product. Thesefall into one of two classes:

1. There are no known or suspected bioequivalence problems.

2. Actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence.

Category "B" consists of drug products that the FDA does not at this time considerto be therapeutically equivalent to the pharmaceutically equivalent reference prod-uct. Certain types of products are rated B by virtue of their specialized dosageforms. For example, controlled-release dosage forms are rated BC, unlessbioequivalence data have been submitted as evidence of equivalence. In this case,the product would be coded AB.

The fact that a product is in the "B" category does not mean it should not be dis-pensed; it simply means that a B rated product should not be substituted for a phar-maceutically equivalent product. For example, glyburide is marketed asMicronase® and DiaBeta® by two different manufacturers. Both these productsare clinically effective, but because bioequivalence between the two has not beenstudied, they are B rated and are not interchangeable.

To avoid possible significant variations among generic drugs as a result of compar-ison to different reference drugs, the FDA began designating a single referencelisted drug against which all generic versions must be shown to be bioequivalent.The reference listed drug is identified by the symbol "+" in the Prescription DrugProduct List. This symbol was used for the first time in the 1993 edition of theOrange Book.

Limitations and exclusions-

Although the Orange Book is a very valuable reference for pharmacists perform-ing drug product selection, it has certain limitations, which must be recognized. Itwas not intended to serve as a single comprehensive reference on all multisourcedrugs. Many prescription drug products are not listed in the Orange Book, makingevaluation of their therapeutic equivalence difficult, if not impossible. Exclusionof a drug from the Orange Book means that the FDA has not evaluated its safety,efficacy and quality. Table 18 lists the classes of products excluded from theOrange Book. Because the equivalence of these excluded products is unknown,interchanging of these products should be avoided.



TABLE 8-18 Drug Products excluded from the Orange Book

Another limitation of the Orange Book that all pharmacists should be aware of isthat the drug listings contain the names of only the companies that actually hold anapproved NDA or ANDA; they may not be the same as the actual manufacturer ordistributor. It is fairly common practice for a drug to be manufactured pursuant toan NDA or an ANDA but distributed under license agreement by another com-pany. In this instance, the distributor would not be listed in the Orange Book.Since pharmacists are, understandably, generally unaware of the name of the actualholder of the NDA or ANDA, it is often difficult for them to determine the thera-peutic equivalence of a particular multisource product if it is not listed in theOrange Book. For example, there are over thirty manufacturers and distributorsmarketing approved, therapeutically equivalent versions of furosemide 40 mg tab-lets (154). However, only twelve of these companies are actually listed in theOrange book, since these are the actual holders of an NDA or ANDA. Therefore,the pharmacist would have to verify the therapeutic equivalence evaluation of thenon-listed products by obtaining the information from the manufacturer, packager,or supplier.

Legal status and pharmacists' responsibility-

The Orange Book per se has no legal status. The FDA stresses that it is a source ofinformation and advice on drug product selection, but it does not mandate the drugproducts which may be dispensed nor the products that should be avoided. Thus,the Orange Book does not carry the weight of regulation or law, and the FDAassumes no liability for drug products selected on the basis of its equivalence eval-uation.

The Orange Book points out that "FDA evaluation of therapeutic equivalence in noway relieves practitioners of their professional responsibilities in prescribing anddispensing such products with due care." There are circumstances where pharma-

1. Drugs marketed before the passage of the Federal Food, Drug, and Cosmetic Act of 1938. These are not included because the FDA has not reviewed these drugs for safety and efficacy and does not have the necessary information to make therapeutic equivalence evaluations.Examples: digoxin, morphine, codeine, thyroid, levothyroxine, phenobarbital and nitroglycerin

2. Drugs for which the FDA has no NDA or ANDA on file. Examples: Anusol-HC®, Naldecon® (and their generic counterparts)

3. Drugs still undergoing Drug Efficacy Study Implementation (DESI) review. These are drugs that were marketed between 1938 and 1962 on the basis of safety, but not efficacy. Although most of these drugs have been reviewed and are listed in the Orange Book, there are still a number of these pre-1962 drugs which have not yet been classified as "effective" under the DESI program, and are not listed.Examples: nitroglycerin controlled-release capsules, pentaerythritol tetranitrate, isocarboxazid,

hydrocortisone-iodochlorhydroxyquin cream

In addition, nitroglycerin transdermal patches are still undergoing efficacy studies, and are not listed in the Orange Book.



cists will have to exercise professional care and sound judgement in selecting adrug product for a particular patient. Although two products may be rated as beingtherapeutically equivalent in the Orange Book, they may not be equally suitablefor a particular patient. Drugs that share the "A" code may still vary in ways thatcould affect patient acceptance. They may differ in shape, color, taste, scoring,configuration, packaging, preservatives, expiration time, and in some instances,labeling. If products with such differences are substituted for each other, there ispotential for patient confusion or decreased patient acceptance. For example, apatient may be sensitive to an inert ingredient in one product that another productdoes not contain. Or, a patient may become confused if the color or shape of aproduct varies from that to which he has become accustomed. A patient may rejectthe administration of a substituted product because of differences in taste orappearance. When such characteristics of a specific product are important in thetreatment of a particular patient, the pharmacist should select a product with theseconsiderations in mind as well as bioequivalence.

Despite its limitations and shortcomings, the Orange Book is a very useful guidefor rational product selection. Pharmacists can utilize the information presentedthere, in combination with sound professional judgment, to make decisions onbehalf of their patients regarding the choice of the most appropriate drug product.



8.3 Drug Product Selection

Multisource drug product selection has become a very important component ofcontemporary pharmacy practice. The National Prescription Audit (NPA) has, forsome years now, been chronicling the heightened role played by pharmacists in theselection of which brand (or generic version) of a multiple-source drug will be dis-pensed to the patient. From 1983 through 1993, the pharmacist's role in selectingbrand or generic products for dispensing has increased dramatically, as shown inTable 19. In the first half of 1993, pharmacists controlled 41% of dispensing deci-sions, as compared to 16% in 1983. It is evident that the substitution trend isstrong and is continuing to gain ground. This expansion of pharmacy's province inbrand choice decisions is the result of several factors: economic pressures forlower prescription costs, repeal of anti- substitution laws and increased acceptanceof generics by patients, physicians and pharmacists. Perhaps the most significantfactor in escalating the overall level of pharmacists' brand choice decisions hasbeen the expiration of the patents of high- volume pioneer brands, as previouslydiscussed. This has resulted in significant expansion in the potential for pharma-cist choice.

TABLE 8-19 Pharmacist’s Brand Selection

Year Percent of all new prescriptions involving pharmacists brand choicea

1983198419851986198719881989199019911992

Jan.-June 1993

1618202325273032343841



8.3.1 CONSIDERATIONS IN SELECTING A MANUFACTURER

The selection of a pharmaceutical manufacturer of a multisource product hasbecome an important professional responsibility for pharmacists. This responsibil-ity has become an especially critical part of a pharmacists role in light of theincreasing number of generic products available and in light of some of the prob-lems that have occurred in the generic drug industry (the "generic drug scandal" of1989). The pharmacist is entrusted by the public to select manufacturers that offerthe best quality at the best price.

So how does the phar-macist select the manu-facturer of a multisource drug product? What factors should be con-sidered?

Thoughtful selection of a multisource drug product is not an easy task, andrequires a consideration of not only the drug product itself, but also the manufac-turer, and in some cases, the patient. Several options are open to the pharmacistperforming drug product selection: to select a product solely on the basis of eco-nomics, to select a product on the basis of the reputation of the manufacturer, or tomake a decision based on product bioequivalence and quality and on the basis ofthe product's conformity with official compendial standards and with those estab-lished by the FDA. The first option, while offering a financial advantage, does notprovide assurance of therapeutic efficacy. The second option, although subjective,is easily applied and does offer a degree of security to the pharmacist. The thirdoption is the most challenging to the pharmacists, requiring the application of prin-ciples of biopharmaceutics and pharmacokinetics in arriving at a decision. Ideally,the pharmacist should take into consideration all the above options when selectinga drug product for a patient.

When pharmacists were asked which factors are most important to them in select-ing a manufacturer of a generic product, the primary criteria indicated were thereputation and quality of the company (159-162). Bioequivalence to thebrand-name product was also ranked as being an important factor in product selec-tion. However, the most frequently used sources for assessing bioequivalencewere manufacturer reputations (based previous experience) and product literatureprovided by the distributing company. Company-sponsored material must be care-fully evaluated. Unfortunately, promotional literature does not generally containsufficient data to permit rational analysis of whether or not products are bioequiva-lent (163). Also, relying on personal methods of information gathering for assess-ing bioequivalence is not very reliable. Interestingly, only 23% of pharmacistsreported using the Orange Book in assessing bioequivalence (161). Selection ofdrug products should be based on sound scientific and clinical grounds. Develop-ments in the science of pharmacokinetics and the related area of bioavailabilityhave given pharmacists the tools necessary to make sound choices among multi-source products. In response to the profession's need for information and adviceon how to select appropriate drug products from multiple sources, the AmericanPharmaceutical Association formed a Bioequivalency Working Group to establishguidelines for product selection (Table 8-20 on page 47) (164). This Group made



recommendations of factors that pharmacists should consider when selecting drugproducts to be dispensed to their patients. If pharmacists consider the factors indi-cated as part of the professional judgement process when making drug productselections, it is likely that the best interest of the patients will be served.

The appropriate selection of a generic drug product involves much more than justcost considerations or reliance on state and federal laws and regulations. Itrequires a knowledge of the drug entity and its physical and chemical properties,the condition to be treated, and its significance, and the history and attitude of themanufacturer. One of the criteria often used to evaluate a manufacturer's record isthe number and type of recalls of that company's products. Product selection mayalso require taking into consideration the patient, the disease, previous drug ther-apy, and duration of therapy before a decision is made. Gagnon presented astep-by-step analysis procedure that pharmacists can use in evaluating multisourcesuppliers of a pharmaceutical product (Table 8-21 on page 49) (165). Using thisprocedure, each manufacturer is rated in each area listed, thus enabling the phar-macist to make the most rational choice.



TABLE 8-20 Guidelines for product selection

DISPENSING DECISIONS

? State Rules and Regulations. Pharmacists should be cognizant of legal requirements that address the issue of drug product selection. Many states have positive or negative formularies to provide guidance in drug product selection.

? Bioequivalency Information/Orange Book Ratings. Only products with proven bioequivalency should be selected to be dispensed in lieu of the innovator product. Products that are listed in the FDA's Approved Drug Products and Therapeutic Equivalence Evaluations (the Orange Book) as "A" rated should be selected when such products are available. For pre-1938 drugs, the selection should be based on data obtained from the literature, because bioequivalency testing is not required by the FDA for these drug products.

? Dosage Form. The type of dosage form should be considered whenever one drug product is selected from among multisource drug products. This is especially true with extended or delayed release medications.

? Previous Drug Use. Two questions should be considered regarding previous drug product usage. First, is the prescribed drug a continuation of already successful therapy? If it is, the impact of any change in source of the medication should be considered. The pharmacist should also know which product the patient was using previously, including any medications in the hospital if the patient was recently discharged. Second, was the original product dispensed a generic product? If so, preference should be given to continuing to dispense the same generic product from the same source.

? Patient Status. The pharmacist should consider how well controlled the patient is and how susceptible that patient might be to small changes in drug absorption. If a patient has labile control or has experienced great difficulty in achieving control, the pharmacist should continue therapy with a product from a single source throughout therapy.

? Diseases. The seriousness of the disease and its potential impact on the patient may influence the pharmacist's willingness to change products.

? Drug Class or Category. Drugs with narrow therapeutic ranges and with known clinically significant bioavailability problems should be substituted with care and/or after discussion with the prescriber.

? Cost. The cost of the product , while an important consideration, should be a secondary consideration in selecting among products judged by the pharmacist to be bioequivalent.

? Patient Opinion. An informed patient, cooperating with a physician and pharmacist in his or her drug therapy, is an important element in ensuring the best possible therapeutic outcomes. The pharmacist should take into account the patient's need when selecting from multisource drug products and inform the patient of any potential consequences associated with alternate product selections.

PURCHASE DECISIONS

? Current State Laws and Regulations. Some states have positive or negative formulary systems that place regulatory restrictions on the products considered therapeutically equivalent. The state formulary may not always be in agreement with classifications listed in the FDA's Orange Book. Therefore, pharmacists should be familiar with both.

? Bioequivalency Information/Orange Book. Products shown to be bioequivalent through reference to the Orange Book or other reliable source of bioequivalency information are preferred. Purchase decisions for drugs marketed prior to 1938 should be based on data obtained from the literature or the manufacturer, because bioequivalency testing may not be required by the FDA for these drug products.

? Drug Category. Greater attention should be given to purchasing strategies for drug products used for serious or life-threatening diseases and in situations where therapeutic activity of the product is confined to a narrow range of biologic fluid concentration.

? Availability. A continuous supply from the same manufacturer is essential even in the event that the distributor has changed to ensure that refills of prescriptions will contain the same product as originally dispensed. However, in those instances when the manufacturer of a generic drug product has to be changed, care should be exercised to ensure that the new drug product is equivalent to the formerly stocked drug product.

? Supplier's Reputation. The reputation of the manufacturer in terms of its ability to adhere to good manufacturing practices (GMP) that ensure that each dosage form is manufactured correctly and in a consistent manner is an important consideration. When purchasing a product from a distributor rather than directly from the manufacturer, the procedure used by that supplier in selecting manufacturers for multisource products is also an important consideration. Establishment Inspection Reports and recall reports are available from FDA through a Freedom of Information (FOI) request. These are valuable tools in this decision.

? Cost.





TABLE 8-21 Evaluation of Multi-source Suppliers

Factors and Cues

Product Information • Size(s) available • Dosage form(s) available • Bioequivalence data results using Orange Book • Existence of identification codes on solid dosage forms • Average number of months between product receipt and expiration date • Results of cost-effectiveness information from manufacturer • Complete product literature provided from manufacturer • Strength(s) available • State/federal formulary rules, e.g., MAC limits

Economics • Price(s) • Deals and other discounts • Terms of sale • Clear and equitable pricing policy • Large sizes available at discount prices

Product Quality • NDA/ANDA on file at FDA • Pharmaceutical elegance of products, e.g., broken tablets, powder in bottles • Less than 3 year FDA on-site inspection • Results of on-site FDA inspection • Company willing to allow pharmacist to inspect plant • Results of quality control analysis • Company willing to supply samples for testing • Product acceptance by physicians • Product acceptance by patients

Service Quality • Returns policy • Rapid resolution of complaints • Company product availability record • Liability protection policy • Terms of unconditional guarantee • Company commitment to education of practitioners • Availability of company representative • Existence of 24-hour emergency customer service telephone number • Product availability through wholesalers • Ease of placing orders • Company customer information center, including an 800 number

Company Reputation • Number of recalls in last 3 years • Severity of recalls in last 3 years • Who initiated recalls (FDA or company) • Company has a recall strategy • Other regulatory actions against company • Company has wide product line • FDA quality assurance profile • Company has crisis communication strategy



Pharmacists have the responsibility of correctly selecting and dispensing multi-source products that will have the greatest likelihood of achieving a positive thera-peutic outcome in a cost-effective manner. The more information pharmacistshave about a product and its manufacturer, the more likely they will be to make themost appropriate choice. Price cannot be the single factor in selecting a product. Itis also clear, as Joseph Oddis stated, "Rational drug product selection entails farmore than simply consulting the FDA's Orange Book or looking at the price cata-logue" (166).

8.3.2 SPECIAL CASES

While in most situations selection of drug products that are therapeutically equiva-lent can be done without undue complications, there are some circumstanceswhere problems could occur. Depending on the drug, its formulation, the diseasebeing treated, and the condition of the patient, generic substitution may not beadvisable. Some of these special situations require extra attention and handling bythe pharmacist.

There are a number of drugs that could present problems when interchanged.Drugs that are poorly water soluble may have inherent problems with rate andextent of dissolution, resulting in poor or variable bioavailability. Drugs that arepotent and thus present in very low amounts in a dosage form could present prob-lems due to formulation factors. Some dosage forms may have inherent bioavail-ability problems, such as controlled-release products. And drugs which areconsidered "critical" also need special consideration. "Critical" drugs have beendefined as drugs with a narrow therapeutic range, where a change in plasma con-centration might result in adverse clinical outcome; drugs that are considered pri-marily for control of a disease rather than for alleviation of temporary symptoms;and drugs that have inherent or historical bioavailability or bioequivalence prob-lems (8, 19). Seven classes of drugs have been identified that have demonstratedbioequivalence problems or, because of the nature of the product, have the poten-tial for creating therapeutic problems if product interchange is permitted (Table 8-22 on page 51) (167-168).



TABLE 8-22 Catagories of drugs with demonstrated bioequivalence problems

There have been numerous reports of drugs implicated in therapeutic problems dueto bioinequivalence difficulties. In addition to those in the categories given inTable 8-22 on page 51, these include furosemide, propranolol, diazepam, pred-nisone, nitrofurantoin, and amitriptyline (20, 126, 167, 169-180). Although thedocumentation implicating these drugs in therapeutic failures due to bioavailabil-ity problems is primarily anecdotal in nature (and thus disregarded by the FDA),the performance of these products should still be closely observed and monitored,and care should be taken when selecting drugs from these categories.

In addition to "critical" drugs, critical patients and critical diseases have also beenidentified when special care should be taken in performing product selection (8,166). Critical patients are the very old and the very young, those suffering frommultiple diseases who are managed with multiple drugs, and those who live alone,making observation of adverse drug effects unlikely. Critical diseases are gener-ally chronic in nature and difficult to stabilize, where drug-disease interactions canpresent major problems (e.g. congestive heart failure, asthma, diabetes, cardiacdisorders, and psychoses). In all the above special "critical" circumstances, thereis a high risk of therapeutic problems, and product selection requires extra atten-tion and precautions. In fact, product substitution and interchange in these cases isgenerally discouraged. Once a product (brand or generic) has been selected for acourse of therapy, the pharmacist should not change to a different product if it canbe avoided. If interchange is performed, it should be done only with the utmostcare, and the patient should be monitored for any adverse outcomes.

Digitalis glycosides - digoxin

Warfarin anticoagulants

Theophylline products

Thyroid preparations (including levothyroxine)

Conjugated and esterified estrogens

Antiarrhythmic agents - quinidine salts

- procainamide

Anticonvulsants- phenytoin- carbamazepine- primidone



Pharmacist's professional responsibility-

Drug product selection has been and continues to be a primary and chal-lenging professional responsibility of pharmacists. It is one where the pharmacistmust exercise professional care and sound judgement to make decisions on behalfof the patient to maximize safety and efficacy, while minimizing cost. Pharmacistshave a professional obligation to patients to take whatever steps are necessary toassure themselves that the medicines they are dispensing are safe and effective.Although some of this activity is currently constrained by bureaucratic and regula-tory restrictions that often discourage, or entirely prevent, individual professionalevaluation and initiative, with a greater appreciation and understanding of the sci-entific, clinical, and regulatory issues that form the basis of the process, pharma-cists can make decisions that result in better patient care. Pharmacists must takesteps to ensure the quality and integrity of the drug products dispensed to theirpatients. To accomplish this, pharmacists must look to pharmaceutical manufac-turers to supply them with a quality product they can trust. Thus, the manufacturerof a multisource product must be carefully selected to ensure that the products theysupply are of proper quality. If necessary, pharmacists should conduct independentresearch into the reputation and integrity of the manufacturer, or, if products arepurchased through a buying group, should make sure that established policies andguidelines are in place to review multisource products. When considering pur-chasing drug products, the pharmacist should request the manufacturer to providecertain documentation and information, and should then evaluate this information(see Table 23).

TABLE 8-23 Considerations when evaluating a Multi-Source vendor

And finally, pharmacists can counsel the patients on the importance ofusing the same drug product throughout a course of therapy, even though theymight go to a different pharmacy. To further emphasize this, it has been suggestedthat the initial prescription and subsequent refills of a drug product consideredquestionable for interchange should contain auxiliary labeling that stresses theimportance of continuing to use that product (167).

Drug product selection is an important professional responsibility, but it isnot an easy task. It requires the pharmacist to use his/her current knowledge, and

1.Willingness to supply requested information

2.Bioavailability and bioequivalence data

3.Dissolution testing results

4.FDA bioequivalence rating

5.The actual manufacturer of the product, if not the supplier

6.FDA inspection reports

7.History of the manufacturer's recall record

8.Willingness of the manufacturer to permit on-site visitations

9.Evaluate economic considerations such as price, shipping, terms, discounts, insurance, return policies, and packagng.



all the currently available information in order to arrive at and render a decisionregarding the most appropriate product to use for a specific patient.



8.4 Summary

With the dramatic increase in the availability and utilization of generic drug prod-ucts in recent years, pharmacists are being faced with an ever-increasing array ofmultisource products. Appropriate selection of a product from the plethora ofproducts on the market is not always an easy task; the quality of the drug productmust be considered, as well as the cost. The principles of biopharmaceutics indi-cate that the formulation and method of manufacture of a drug product can have amarked effect on the bioavailability of the active ingredient. Thus, generic equiva-lents may not necessarily be therapeutically equivalent. Guidelines and criteriahave been established by the FDA to help judge whether one product can be sub-stituted for another with assurance of equivalent therapeutic effect.

For pharmacists to provide informed product selection, it is essential thatthey be knowledgeable about, and familiar with, these guidelines and criteria. Thisrequires an understanding of bioavailability, bioequivalence, and how they aredetermined. The pharmacist can serve a major role in ensuring that only high qual-ity products are dispensed, and in this way help reduce health care costs withoutcompromising quality of care.

Acknowledgment The author gratefully acknowledges the assistance of Umesh V. Banakar in thepreparation of this manuscript.



8.4.1 QUESTIONS

1. The term bioavailability refers to the

a. dissolution of a drug in the gastrointestinal tract.

b. amount of drug destroyed in the liver by first-pass metabolism.

c. distribution of drug to the body tissues over time.

d. relationship between the physical and chemical properties of a drug and its systemic absorption.

e. measurement of the rate and amount of drug that reaches the systemic circulation.

2. The bioavailability of various drug products can be evaluated by comparing their plasma con-centration-time curves. The three most important parameters of comparison that can be obtained directly from the curves are

a. biologic half-life (t1/2), absorption rate constant, area under the curve (AUC).

b. time of peak concentration (tmax), absorption rate constant, elimination rate constant.

c. maximum drug concentration (Cmax), time of peak concentration (tmax), duration of action.

d. area under the curve (AUC), time of peak concentration (tmax), maximum drug concentration

(Cmax).

e. rate of elimination, area under the curve (AUC), rate of absorption.

3. Two products are bioequivalent if they

a. contain the same amount of the same active ingredient.

b. have equal areas under the curve after the administration of the same dose.

c. have the same value for Cmax after administration of the same dose.

d. have equivalent rates and extents of absorption of the drug after administration of equal doses.

e. are pharmaceutically equivalent.

4. If an oral capsule formulation of drug A produces a plasma concentration- time curve having the same area under the curve (AUC) as that produced by an equivalent dose of drug A given intravenously, it can generally be concluded that:

a. there is no advantage to the IV route.

b. the absolute bioavailability of the capsule formulation is equal to 1.

c. the capsule formulation is essentially completely absorbed.

d. the drug is very rapidly absorbed.

e. b and c are correct.

5. 5.Which of the following is NOT a criterion for therapeutic equivalence of two products, according to the FDA?

a. They must be pharmaceutical equivalents.



b. All ingredients - active and inactive - must be the same.

c. They have been manufactured in compliance with Good Manufacturing Practices.

d. They are bioequivalent.

e. They are approved as safe and effective by the FDA.

6. A test oral formulation has the same area under the plasma concentration- time curve as the ref-erence formulation. This means that the two formulations

a. are bioequivalent by definition.

b. deliver the same total amount of drug to the body but are not necessarily bioequivalent.

c. are bioequivalent if they both meet USP dissolution standards.

d. deliver the same total amount of drug to the body and are, therefore, bioequivalent.

e. have the same rate of absorption.

7. In-vitro dissolution rate studies on drug products are useful in bioavailability evaluations only if they can be correlated with

a. in-vivo bioavailability studies in humans.

b. the chemical stability of the drug.

c. USP disintegration requirements.

d. in-vivo studies in at least three species of animals.

e. the therapeutic response observed in patients.

8. Which of the following statements regarding bioequivalence is TRUE?

a. If the mean AUC and Cmax values for a generic product are within + 20% of those of the ref-erence product, the two products are bioequivalent.

b. If we can be 90% certain that the mean values of AUC and Cmax for two products are within

80% to 125% of each other, then the two products are considered bioequivalent.

c. Bioequivalence studies are generally conducted in a panel of patients consisting of the tar-get population for which the drug is intended.

d. Bioequivalence studies are generally conducted as multiple-dose studies utilizing the cross-over design.

e. If two products are shown to be bioequivalent, we can always say with certainty that they will be therapeutically equivalent.



9. 9.Which of the following statements about the FDA Orange Book is TRUE?

a. Drugs that are excluded from the Orange Book are not safe and effective and should not be dispensed.

b. It contains therapeutic equivalence evaluations for all the drugs approved by the FDA.

c. Products placed in the "B" category should not be dispensed.

d. The Orange Book is an official compendium, and pharmacists can legally only dispense those products listed as bioequivalent.

e. The drug listings contain the names of only the companies that actually hold an approved NDA or ANDA for a drug.

10. 10.Growth in the utilization of generic drug products can be attributed to

a. passage of the 1984 Waxman-Hatch Act.

b. expiration of patents of many popular brand products.

c. pressures to reduce health care costs.

d. the growth of managed health care organizations.

e. all of the above.

8.4.2 ANSWERS TO QUESTIONS

1. e

2. d

3. d

4. e

5. b

6. b

7. a

8. b

9. e

10. e



8.5 Bioavailibility Equations

The following set of equations were used to solve the bioavailability problem set.The problem sets for the first two drugs have been done for you. The others aredone exactly the same way. The answers follow the problems.

1. as discussed in chapter 4.

2.

3.

4.

5.

6.

7.

8. as discussed in chapter 4

9.

10.

11.

MRT iv

AUMCiv

AUCiv

---------------------=

k 1MRTiv

----------------=

t1 2⁄2ln

k--------=

Cp0iv AUC k⋅=

Vd

Dose iv

Cp0iv

-----------------=

Cpiv Cp0ekt–

=

fAUCoral

Doseoral

---------------------Doseiv

AUCiv

-----------------⋅=

MRTpo

AUMCpo

AUCpo

-----------------------=

MATpo MRTpo MRTiv–=

ka1

MAT------------=

tp

ka

k-----

ln

ka k–----------------=



12.

14. Relative Bioavailability (R.B. or C.B.) =

15. Bioequivalent: Yes if all three:

CpmaxfDV------

ka

ka k–------------- e

ktp–e

katp––( )⋅ ⋅=

AUCgeneric( ) Dosegeneric( )⁄AUCBrand( ) DoseBrand( )⁄

----------------------------------------------------------------------

0.80 CB 1.25< <

0.80tpgeneric

tpbrand

-------------- 1.25< <

0.80Cpmax g– eneric

Cpmax b– rand

------------------------ 1.25< <



8.6 Problems



Caffeine (Problem 8 - 1)

Aramaki, S., et al., "Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular, or oral adminis-tration", Chem Pharm Bull, Vol. 30, No. 11, (1991), p. 2999 - 3002.

This study deals with the pharmacokinetics of caffeine. Caffeine doses of 2.5 mg/kg were administered both intrave-nously and orally to horses with an average weight of about 500 kg. A summary of the some of data obtained from thisexperiment is given below. Fill in the empty cells.

Problem Submitted By: Maya Leicht AHFS 00:00.00Problem Reviewed By: Vicki Long GPI: 0000000000

TABLE 8-24 Caffeine

Parameter IV Oral Solution Brand Tablet Generic Tablet Bioequivalence

Dose (mg/kg) 2.5 2.5 2.5 2.5

AUC 63.1 60.7 60 57

AUMC 1442 1556.8 1600 1723

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)

Relative Bioavailability

Generic Equivalent (Yes / No)

ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



Cefetamet Pivoxil (Problem 8 - 2)

Ducharme, M., et. al., "Bioavailability of syrup and tablet formulations of cefetamet pivoxil", Antimicrobial Agents and Chemo-therapy, Vol. 37, No. 12, (1993), p. 2706 - 2709.

Cefetamet pivoxil is a prodrug of cefetamet. This study compares the bioavailability of cefetamet pivoxil in tabletform versus syrup form. A summary of the some of data obtained from this experiment is given below. Fill in theapproprate cells.

.



Dose (mg) 250 500 500 500

AUC 30.64 53.68 50 47

AUMC 101.66 191.64 205.6 225.3

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



Cefixime (Problem 8 - 3)

Faulkner, R. ,et al., "Absolute bioavailability of cefixime in man", Journal of Clinical Pharmacology, Vol. 28 (1988), p. 700 - 706.

Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram nega-tive bacteria. In this study, sixteen subjects each received a 200 mg intravenous dose and then a 200 mg capsule with awashout period between the administration of each dosage form. A summary of the some of data obtained from thisexperiment is given below.

From the preceding data, please calculate the following:


Parameter IV Brand Capsule Generic Capsule Bioequivalence

Dose (mg) 200 200 200

AUC 47 23.6 20.2

AUMC 183.3 162.8 187.5

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



Ceftibuten (Problem 8 - 4)

"The pharmacokinetics of ceftibuten in humans"

Ceftibuten is a new oral cephalosporin with potent activity against enterobacteriaceae and certain gram posi-tive organisms. In this study two groups received either a 400 mg oral dosage form of ceftibuten or a 200 mg iv bolusdose of ceftibuten. A summary of the some of data obtained from this experiment is given below.




Dose (mg) 200 400 400 400

AUC 75.2 65.9 64.2 64

AUMC 211.2 213.4 220 208

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



Cimetidine (Problem 8 - 5)

Sandborn, W., et al., "Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients", Jour-nal of Clinical Pharmacology, Vol. 30, (1990), p. 568 - 571.

Cimetidine is a histamine receptor antagonist which is used in the treatment of gastric and duodenal ulcer dis-ease. In this study, patients received 300 mg of cimetidine as an iv bolus on the first day and data was collected. Onthe second day, the patients received 300 mg orally and data was collected. A summary of the some of data obtainedfrom this experiment is given below.


Parameter IV Brand Tablet Generic Tablet Bioequivalence

Dose (mg) 300 300 300

AUC 3.81 2.48 2.50

AUMC 5.33 11.73 10.73

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



Diurnal Variability in Theophylline Bioavailability (Problem 8 - 6)

Bauer, L., Gibaldi, M., and Vestal, R., "Influence of pharmacokinetic diurnal variation on bioavailability estimates", Clinical Phar-macokinetics, vol. 9, (1984), p. 184 - 187.

This article discusses the effects of diurnal variation on the bioavailability and clearance of theophylline. Inthis study patients received a 500 mg dose every 12 hours either orally or by iv bolus. A summary of the some of dataobtained from this experiment for the time period between midnight and noon is given below.




Dose (mg) 500 500 500 500

AUC 160.25 144.58 140 144

AUMC 1821 1662 1785 1700

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



cis-5-Fluoro-1-[2-Hydroxymethyl-1,3-Oxathiolan-5-yl] Cytosine (FTC) (Problem 8 - 7)

Frick, L. , et al., "Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-Fluoro-1-[2-Hydroxyme-thyl-1,3-Oxathiolan-5-yl] Cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus", Anti-microbial Agents and Chemotherapy, Vol. 37, No. 11, (1993), p. 2285 - 2292.

FTC is a 2',3'-didoexynucleoside analog that may be useful against HIV and HBV. In this study, rats with anaverage weight of 270 g were given either iv or oral doses of 100 mg/kg. A summary of the some of data obtainedfrom this experiment is given below.




Dose (mg/kg) 100 100 100

AUC 265 168 175

AUMC 19514 12600 13125

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



Hydromorphone (Problem 8 - 8)

Vallner, J., et al., "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects", Journal of Clinical Pharmacology, Vol. 21, (1981), p. 152 - 156.

Hydromorphone hydrochloride is an analog of morphine which has about seven times the effect of morphinewhen given intravenously. In this study, volunteers were given a 2 mg intravenous dose and a 4 mg oral dose of hydro-morphone on separate days. A summary of the some of data obtained from this experiment is given below.




Dose (mg) 2 4 4

AUC 83 87.2 96

AUMC 289.4 401 432

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugL------ hr⋅

ugL

------ hr2⋅

ugL------

ugL------

ugL

------



Isosorbide Dinitrate (Problem 8 - 9)

Straehl, P. and Galeazzi, R., "Isosorbide dinitrate bioavailability , kinetics, and metabolism", Clinical Pharmacology and Thera-peutics, Vol. 38m (1985), p. 140 - 149.

Isosorbide dinitrate is used in the treatment of angina pectoris, vasospastic angina, and congestive heart failure.In this study volunteers received a 5 mg intravenous dose given over 5 minutes and a 10 mg tablet. The different dos-age forms were separated by a washout period. A summary of the some of data obtained from this experiment is givenbelow.




Dose (mg/kg) 5 10 10

AUC 370.3 158 165

AUMC 487 310 305

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugL------ hr⋅

ugL

------ hr2⋅

ugL------

ugL------

ugL

------



Ketanserin (Problem 8 - 10)

Kurowski, M., "Bioavailability and pharmacokinetics of ketanserin in elderly subjects", Journal of Clinical Pharmacology, Vol. 28, (1988), p. 700 - 706.

Ketanserin is a 5-hydroxytryptamine S2-antagonist. This study focuses on the kinetics of Ketanserin in theelderly. Subjects were given either a 10 mg intravenous dose or a 40 mg oral tablet. A summary of the some of dataobtained from this experiment is given below.




Dose (mg) 10 40 40

AUC 247 520 400

AUMC 3991 8922 8922

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



Methotrexate (Problem 8 - 11)

Seideman, P., et al., " The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis", British Journal of Clinical Pharmacology, 35 (1993), p. 409 - 412.

The drug Methotrexate is a folic acid which has been shown to inhibit dihydrofolate reductase. The impor-tance of this drug at present is mostly seen in the area of oncology, but lately it has been used for rheumatoid arthritis.Methotrexate has a molecular weight of 454.4. In this study, the drug was administered both by IV bolus and orally asa 15 mg dose. The following data was obtained:




Dose (mg) 15 15 15

AUC 2752 2708 2700

AUMC 15887 18400 18500

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



nmoleL

---------------- hr⋅

nmoleL

---------------- hr2⋅

nmoleL

----------------

nmoleL

----------------

nmoleL

----------------



Moclobemide (Problem 8 - 12)

Schoerlin, M. et al., "Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function", Jour-nal of Clinical Pharmacology, Vol. 30 (1991), p. 272 - 284.

Moclobemide is an antidepressant agent that reversibly inhibits the A-isozyme of the monoamine oxidaseenzyme system. In this study, single IV and oral doses were administered to a patient. A summary of the some of dataobtained from this experiment is given below.




Dose (mg) 150 100 100

AUC 2.58 1.70 1.52

AUMC 6.35 5.91 5.90

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



Nalbuphine (Problem 8 - 13)

Nalbuphine hydrochloride is an agonist-antagonist opiod which is used for its analgesic actions. In this study,volunteers were given single doses of four different nalbuphine forms. The data below focuses on a 10 mg iv dose anda 45 mg dose of an oral solution. A summary of the some of data obtained from this experiment is given below.




Dose (mg) 10 45 40 40

AUC 86.9 70.3 62.5 60

AUMC 288 306 280 270

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



Nefazodone (Problem 8 - 14)

Shukla, U. et al., "Pharmacokinetics, absolute bioavailability, and disposition of nefazodone in the dog", Drug Metabolism and Disposition, Vol. 21, No. 3, (1993), p. 502 - 507.

Nefazodone was given to four healthy, adult, male beagles with an average weight of 11.0 kg. Each dog wasgiven a 10 mg/kg dose as a either a intravenous injection or as an oral solution or tablet. A summary of the some ofdata obtained from this experiment is given below.




Dose (mg/kg) 10 10 10 10

AUC 6023 829 800 700

AUMC 29283 4875 4800 4500

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



Ondansetron (Problem 8 - 15)

Colthup, P., et al., "Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly", Journal of Phar-maceutical Sciences, Vol. 80, No. 9(1991), p. 868 - 871.

Ondansetron is a 5-hydroxyltryptamine compound which is useful in treating the nausea and vomiting which iscaused by the use of chemotherapy and radiation in the cancer patients. In order to determine the absolute bioavailabil-ity of oral Ondansetron, doses of 8 mg were given to two groups. One group received an oral dose and the other groupreceived an intravenous dose. A summary of the some of data obtained from this experiment is given below.




Dose (mg) 8 8 8

AUC 246.5 139 145

AUMC 1138 795 870

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



Omeprazole (Problem 8 - 16)

Anderson, T., et al, "Pharmacokinetics of various single intravenous and oral doses of omeprazole", Eur Journal of Clinical Phar-macology, 39, (1990), p. 195 - 197.

Omeprazole (mw: 345.42) is an agent which inhibits gastric acid secretion from the parietal cell. It is useful intreating such problems as ulcers and gastroesophageal reflux disease. One group received an iv bolus dose and theother group received an oral dose. A summary of the some of data obtained from this experiment is given below.




Dose (mg) 20 40 40

AUC 3.2 3.5 3.0

AUMC 3.2 5.25 4.5

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



µmoleL

---------------- hr⋅

µmoleL

---------------- hr2⋅

µmoleL

----------------

µmoleL

----------------

µmoleL

----------------



Paroxetine (Problem 8 - 17)

Lund, J., et al., "Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man", Journal of Pharmacology and Toxicology, Vol. 51, (1982), p. 351 - 357.

Paroxetine kinetics and cardiovascular effects were studied in male subjects after single oral doses of 45 mgand slow intravenous infusion of 23 - 28 mg. A summary of the some of data obtained from this experiment is givenbelow.




Dose (mg) 28 45 45

AUC 467 750 675

AUMC 6671 11250 10463

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



Ranitidine (Problem 8 - 18)

Garg, D., et al., "Pharmacokinetics of ranitidine in patients with renal failure", Journal of Clinical Pharmacology, Vol. 26 (1986), p. 286 - 291.

Ranitidine is an agent used in the treatment of peptic ulceration. In this study, ten patients with renal failurereceived either a 50 mg intravenous bolus dose or a 150 mg tablet. A summary of the some of data obtained from thisexperiment is given below.




Dose (mg) 50 150 150

AUC 5159 6422 6753

AUMC 53415 78752 84413

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



Sulpiride (Problem 8 - 19)

Bressolle, F., Bres, J., and Faure-Jeantis, A., "Absolute bioavailability , rate of absorption, and dose proportionality of sulpiride in humans", Journal of Pharmaceutical Sciences ,Vol. 81, No. 1 (1992), p. 26 - 32.

Sulpiride is a substituted benzamine antipsychotic. In this study, the drug was administered to two groups.The first group received a 200 mg oral dose and the second group received a 100 mg intravenous infusion. A summaryof the some of data obtained from this experiment is given below.




Dose (mg) 100 200 200 200

AUC 8.27 8.79 8.6 8.0

AUMC 79.1 87.3 91.1 84.5

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



8.7 Solutions

8.7.1 “CAFFEINE” ON PAGE 61

Aramaki, S., et al., "Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular, or oral adminis-tration", Chem Pharm Bull, Vol. 30, No. 11, (1991), p. 2999 - 3002.

This study deals with the pharmacokinetics of caffeine. Caffeine doses of 2.5 mg/kg were administered both intrave-nously and orally to horses with an average weight of about 500 kg. A summary of the some of data obtained from thisexperiment is given below. Fill in the empty cells.

TABLE 8-25 Caffeine


Dose (mg/kg) 2.5 2.5 2.5 2.5

AUC 63.1 60.7 60 57

AUMC 1442 1556.8 1600 1723

MRT (hr) 22.9 25.7 26.7 30.2

MAT (hr) 2.79 3.81 7.36

ke (hr-1) 0.0438

ka (hr-1) 0.358 0.262 0.136

Cp0 2.76

Vd (L/kg) 0.91

Cp at 1 hour 2.64 0.78 0.59 0.31

f 0.96 0.95 .90

Cpmax 2.76 1.98 1.83 1.45 0.79

Tmax (hr) 6.69 8.19 12.1 1.5

Relative Bioavailability 0.95

Generic Equivalent (Yes / No) NO

ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



1. = hours

2. = = 0.044

3. =

4. = 63.1

5. The horses have an average weight of 500 kg.

6.

7.

8.

Where AUMC is that which is given for the oral dose.

Where AUC is that which is given for the oral dose.

9. =

MRT AUMCAUC

------------------=1442ug h

2⋅mL

----------------

63.1ug h2⋅

mL----------------

---------------------------- 22.9=

k 1MRT------------= 1

22.9h------------- h

1–

t1 2⁄2ln

k--------= 0.693

0.044h1–

--------------------- 15.75h=

Cp0 AUC k⋅= ug h⋅mL

------------- 0.0044h1–⋅ 2.76 ug

mL--------=

Dose 2.5mgkg------- 500kg⋅ 1250mg= =

Cp0 2.78 ugmL--------= 2.78mg

L-------=

VdDoseCp0

------------- 1250mg

2.78mgL

--------------------------- 449.6L 2.5mg kg⁄

2.78mgL

-------------------------------- 0.91 L

kg------=== = =

Cp Cp0ekt–

2.78 ugmL--------

e0.044 1( )–( ) 2.64 ug

mL--------= = =

fAUCoral

Doseoral

---------------------Doseiv

AUC iv

-----------------⋅60ug h⋅

mL-------------

2.5mgkg-------

--------------------2.5mg

kg-------

63.1ug h⋅mL

-------------------------------------⋅ 0.95= = =

MRTpoAUMCAUC

------------------1556.8ug h

2⋅mL

----------------

60.7ug h⋅mL

---------------------------------------------- 25.7h= = =

MATpo MRTpo MRTiv–= 25.7h 22.9h– 2.79h=



10.

11.

12.


14. Bioequivalent: Yes if all three = Yes:

CB = 0.95 = Yes

= NO

= NO

ka1

MAT------------ 1

2.79---------- 0.358hr

1–= = =

tp

ka

k-----

ln

ka k–----------------

0.358hr1–

0.044h1–

------------------------

ln

0.358hr1–

0.044hr1–

–------------------------------------------------------ 6.7hr= = =

CpmaxfDV------ ka

ka k–-------------- e

ktp–e

katp–( )⋅ ⋅ 0.96 1250mg⋅

449L----------------------------------- 0.358hr

1–

0.358 0.044–( )hr1–

------------------------------------------------- e0.044 6.7⋅( )–

e0.358 6.7⋅( )–⋅( )⋅ ⋅= =


----------------------------------------------------------------------

CB

57 ugmL-------- hr⋅

2.5mg

km-------

⁄

60 ugmL-------- hr⋅

2.5mg

km-------

⁄------------------------------------------------------------- 0.95==

0.80 CB 1.25< <

0.80tpgeneric

tpbrand

-------------- 1.25< <tpgeneric

tpbrand

-------------- 12.1hr8.19hr---------------- 1.5= =


Cpmax b– rand

------------------------ 1.25< <Cpmax g– eneric

Cpmax b– rand

------------------------1.45 ug

mL--------

1.83 ugmL--------

------------------- 0.79= =



8.7.2 “CEFETAMET PIVOXIL” ON PAGE 62

Ducharme, M., et. al., "Bioavailability of syrup and tablet formulations of cefetamet pivoxil", Antimicrobial Agents and Chemo-therapy, Vol. 37, No. 12, (1993), p. 2706 - 2709.

Cefetamet pivoxil is a prodrug of cefetamet. This study compares the bioavailability of cefetamet pivoxil in tabletform versus syrup form. A summary of the some of data obtained from this experiment is given below. Fill in theapproprate cells.

.

1. = hours

Where AUMC is that which is given for the intravenous dose.

Where AUC is that which is given for the intravenous dose.


Dose (mg) 250 500 500 500

AUC 30.64 53.68 50 47

AUMC 101.66 191.64 205.6 225.3

MRT (hr) 3.32 3.57 4.11 4,79

MAT (hr) 0.252 0.794 1.48

ke (hr-1) 0.301

ka (hr-1) 3.97 1.26 0.678

Cp0 9.23

Vd (L) 27.1

Cp at 1 hour 6.83 12.62 9.03 5.91

f 0.88 0.82 0.77

Cpmax 9.23 13.1 9.6 7.4 0.77

Tmax (hr) 0.70 1.49 2.15 1.44



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------

MRT AUMCAUC

------------------=101.66mg h

2⋅L

-----------------

30.64mg h2⋅

L-----------------

---------------------------------- 3.32=



2. = = 0.301

3. =

4. = 30.64

5.

6.

7.

8.

Where AUMC is that which is given for the oral dose.

Where AUC is that which is given for the oral dose.

9. =

10.

11.

12.


k 1MRT------------= 1

3.32h------------- h

1–

t1 2⁄2ln

k--------= 0.693

0.301h1–

--------------------- 2.3h=

Cp0 AUC k⋅= mg h⋅L

--------------- 0.301h1–⋅ 9.22mg

L-------=

VdDoseCp0

------------- 250mg

9.24mgL

------------------------- 27.06L= = =

Cp Cp0ekt–

9.24mgL

------- e

0.301 1( )–( ) 6.84mgL

-------= = =

fAUCoral

Doseoral

---------------------Doseiv

AUCiv

-----------------⋅53.68mg h⋅

L---------------

500mg----------------------------- 250mg

30.64mg h⋅L

--------------------------------------------⋅ 0.876= = =

MRTpoAUMCAUC

------------------191.64mg h

2⋅L

-----------------

53.68mg h⋅L

------------------------------------------------- 3.57h= = =

MATpo MRTpo MRTiv–= 3.57h 3.32h– 0.252hr=

ka1

MAT------------ 1

0.252------------- 3.97hr

1–= = =

tp

ka

k-----

ln

ka k–----------------

4.0h1–

0.301h1–

---------------------

ln

4.0h1–

0.301h1–

–------------------------------------------- 0.7h= = =

CpmaxfDV------ ka

ka k–-------------- e

kt–e

ka t––( )⋅ ⋅ 0.88 500mg( )

27.1L-------------------------------- 3.97hr

1–

3.97 0.301–( )hr1–

---------------------------------------------- e0.301 0.7( )–

e3.97 0.7( )–

–( )⋅ ⋅ 13.1mgL

-------= = =


----------------------------------------------------------------------



14. Bioequivalent: Yes if all three = Yes:

CB = 0.94 = Yes

= NO

= NO

CB

47 ugmL-------- hr⋅

500mg⁄

50 ugmL-------- hr⋅

500mg⁄-------------------------------------------------------- 0.94==

0.80 CB 1.25< <

0.80tpgeneric

tpbrand

-------------- 1.25< <tpgeneric

tpbrand

-------------- 2.15hr1.49hr---------------- 1.44= =


Cpmax b– rand

------------------------ 1.25< <Cpmax g– eneric

Cpmax b– rand

------------------------7.4 ug

mL--------

9.6 ugmL--------

---------------- 0.77= =



8.7.3 “CEFIXIME” ON PAGE 63

Faulkner, R. ,et al., "Absolute bioavailability of cefixime in man", Journal of Clinical Pharmacology, Vol. 28 (1988), p. 700 - 706.

Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram nega-tive bacteria. In this study, sixteen subjects each received a 200 mg intravenous dose and then a 200 mg capsule with awashout period between the administration of each dosage form. A summary of the some of data obtained from thisexperiment is given below.



Dose (mg) 200 200 200

AUC 47 23.6 20.2

AUMC 183.3 162.8 187.5

MRT (hr) 3.9 6.9 9.3

MAT (hr) 3.0 5.38

ke (hr-1) 0.256

ka (hr-1) 0.334 0.186

Cp0 12.1

Vd (L) 16.6

Cp at 1 hour 9.3 1.5 0.77

f 0.50 0.43

Cpmax 12.1 2.5 1.6 0.64

Tmax (hr) 3.4 4.6 1.33



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



8.7.4 “CEFTIBUTEN” ON PAGE 64

"The pharmacokinetics of ceftibuten in humans"

Ceftibuten is a new oral cephalosporin with potent activity against enterobacteriaceae and certain gram posi-tive organisms. In this study two groups received either a 400 mg oral dosage form of ceftibuten or a 200 mg iv bolusdose of ceftibuten. A summary of the some of data obtained from this experiment is given below.



Dose (mg) 200 400 400 400

AUC 75.2 65.9 64.2 64

AUMC 211.2 213.4 220 208

MRT (hr) 2.94 3.24 3.43 3.25

MAT (hr) 0.297 0.485 0.309

ke (hr-1) 0.390

ka (hr-1) 3.37 2.06 3.24

Cp0 25.6

Vd (L) 7.8

Cp at 1 hour 18.2 16.9 15.3 16.4

f 0.44 0.42 0.43

Cpmax 25.6 17.3 15.3 16.7 1.09

Tmax (hr) 0.76 1.05 0.78 0.74

Relative Bioavailability 1


ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



8.7.5 “CIMETIDINE” ON PAGE 65

Sandborn, W., et al., "Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients", Jour-nal of Clinical Pharmacology, Vol. 30, (1990), p. 568 - 571.

Cimetidine is a histamine receptor antagonist which is used in the treatment of gastric and duodenal ulcer dis-ease. In this study, patients received 300 mg of cimetidine as an iv bolus on the first day and data was collected. Onthe second day, the patients received 300 mg orally and data was collected. A summary of the some of data obtainedfrom this experiment is given below.


Dose (mg) 300 300 300

AUC 3.81 2.48 2.50

AUMC 5.33 11.73 10.73

MRT (hr) 1.40 4.73 4.29

MAT (hr) 3.33 2.89

ke (hr-1) 0.715

ka (hr-1) 0.300 0.346

Cp0 2.72

Vd (L) 110

Cp at 1 hour 1.33 0.32 0.37

f 0.65 0.66

Cpmax 2.72 0.40 0.44 1.1

Tmax (hr) 2.1 2.0 0.94

Relative Bioavailability 1

Generic Equivalent (Yes / No) YES

ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



8.7.6 “DIURNAL VARIABILITY IN THEOPHYLLINE BIOAVAILABILITY” ON PAGE 66

Bauer, L., Gibaldi, M., and Vestal, R., "Influence of pharmacokinetic diurnal variation on bioavailability estimates", Clinical Phar-macokinetics, vol. 9, (1984), p. 184 - 187.

This article discusses the effects of diurnal variation on the bioavailability and clearance of theophylline. Inthis study patients received a 500 mg dose every 12 hours either orally or by iv bolus. A summary of the some of dataobtained from this experiment for the time period between midnight and noon is given below.



Dose (mg) 500 500 500 500

AUC 160.25 144.58 140 144

AUMC 1821 1662 1785 1700

MRT (hr) 11.40 11.50 12.75 11.8

MAT (hr) 0.13 1.39 0.44

ke (hr-1) 0.088

ka (hr-1) 7.58 0.721 2.26

Cp0 14.1

Vd (L) 35.5

Cp at 1 hour 12.9 11.8 6.02 10.7

f 0.90 0.87 0.90

Cpmax 14.1 12.1 9.20 11.1 1.21

Tmax (hr) .059 3.3 1.5 0.45



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



8.7.7 “CIS-5-FLUORO-1-[2-HYDROXYMETHYL-1,3-OXATHIOLAN-5-YL] CYTOSINE (FTC)” ON PAGE 67

Frick, L. , et al., "Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-Fluoro-1-[2-Hydroxyme-thyl-1,3-Oxathiolan-5-yl] Cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus", Anti-microbial Agents and Chemotherapy, Vol. 37, No. 11, (1993), p. 2285 - 2292.

FTC is a 2',3'-didoexynucleoside analog that may be useful against HIV and HBV. In this study, rats with anaverage weight of 270 g were given either iv or oral doses of 100 mg/kg. A summary of the some of data obtainedfrom this experiment is given below.



Dose (mg/kg) 100 100 100

AUC 265 168 175

AUMC 19514 12600 13125

MRT (hr) 73.6 75 75

MAT (hr) 1.36 1.36

ke (hr-1) .0136

ka (hr-1) 0.734 0.734

Cp0 3.6

Vd (L/kg) 27.7

Cp at 1 hour 3.55 1.18 1.23

f 0.63 0.66

Cpmax 3.6 2.1 2.2 1.04

Tmax (hr) 5.54 5.54 1.0



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



8.7.8 “HYDROMORPHONE” ON PAGE 68

Vallner, J., et al., "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects", Journal of Clinical Pharmacology, Vol. 21, (1981), p. 152 - 156.

Hydromorphone hydrochloride is an analog of morphine which has about seven times the effect of morphinewhen given intravenously. In this study, volunteers were given a 2 mg intravenous dose and a 4 mg oral dose of hydro-morphone on separate days. A summary of the some of data obtained from this experiment is given below.



Dose (mg) 2 4 4

AUC 83 87.2 96

AUMC 289.4 401 432

MRT (hr) 3.49 4.60 4.50

MAT (hr) 1.11 1.03

ke (hr-1) 0.287

ka (hr-1) 0.899 0.987

Cp0 23.8

Vd (L) 84

Cp at 1 hour 17.9 12.6 14.7

f 0.53 0.56

Cpmax 23.8 14.6 16.6 1.13

Tmax (hr) 1.87 1.77 0.95



ugL------ hr⋅

ugL

------ hr2⋅

ugL------

ugL------

ugL

------



8.7.9 “ISOSORBIDE DINITRATE” ON PAGE 69

Straehl, P. and Galeazzi, R., "Isosorbide dinitrate bioavailability , kinetics, and metabolism", Clinical Pharmacology and Thera-peutics, Vol. 38m (1985), p. 140 - 149.

Isosorbide dinitrate is used in the treatment of angina pectoris, vasospastic angina, and congestive heart failure.In this study volunteers received a 5 mg intravenous dose and a 10 mg tablet. The different dosage forms were sepa-rated by a washout period. A summary of the some of data obtained from this experiment is given below.



Dose (mg/kg) 5 10 10

AUC 370.3 158 165

AUMC 487 310 305

MRT (hr) 1.32 1.96 1.85

MAT (hr) 0.65 0.53

ke (hr-1) 0.760

ka (hr-1) 1.546 1.875

Cp0 282

Vd (L) 17.75

Cp at 1 hour 132 60.1 66.2

f 0.21 0.22

Cpmax 282 60.4 67.8 1.12

Tmax (hr) 0.90 0.81 0.90



ugL------ hr⋅

ugL

------ hr2⋅

ugL------

ugL------

ugL

------



8.7.10 “KETANSERIN” ON PAGE 70

Kurowski, M., "Bioavailability and pharmacokinetics of ketanserin in elderly subjects", Journal of Clinical Pharmacology, Vol. 28, (1988), p. 700 - 706.

Ketanserin is a 5-hydroxytryptamine S2-antagonist. This study focuses on the kinetics of Ketanserin in theelderly. Subjects were given either a 10 mg intravenous dose or a 40 mg oral tablet. A summary of the some of dataobtained from this experiment is given below.



Dose (mg) 10 40 40

AUC 541 112.5 103.9

AUMC 11700 24900 22900

MRT (hr) 21.6 22.1 22.0

MAT (hr) 0.5 0.4

ke (hr-1) 0.0402

ka (hr-1) 2.0 2.5

Cp0 25.0

Vd (L) 400

Cp at 1 hour 23.9 43.6 42.7

f .052 0.48

Cpmax 25.0 47.6 44.5 0.94

Tmax (hr) 1.93 1.63 0.84



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



8.7.11 “METHOTREXATE” ON PAGE 71

Seideman, P., et al., " The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis", British Journal of Clinical Pharmacology, 35 (1993), p. 409 - 412.

The drug Methotrexate is a folic acid which has been shown to inhibit dihydrofolate reductase. The impor-tance of this drug at present is mostly seen in the area of oncology, but lately it has been used for rheumatoid arthritis.Methotrexate has a molecular weight of 454.4. In this study, the drug was administered both by IV bolus and orally asa 15 mg dose. The following data was obtained:



Dose (mg) 15 15 15

AUC 2752 2708 2700

AUMC 15887 18400 18500

MRT (hr) 5.77 6.79 6.85

MAT (hr) 1.02 1.08

ke (hr-1) 0.173

ka (hr-1) 0.979 0.927

Cp0 477

Vd (L) 69.3

Cp at 1 hour 401 265 256

f 0.98 0.98

Cpmax 477 323 318 0.98

Tmax (hr) 2.15 2.23 1.04



nmoleL

---------------- hr⋅

nmoleL

---------------- hr2⋅

nmoleL

----------------

nmoleL

----------------

nmoleL

----------------



8.7.12 “MOCLOBEMIDE” ON PAGE 72

Schoerlin, M. et al., "Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function", Jour-nal of Clinical Pharmacology, Vol. 30 (1991), p. 272 - 284.

Moclobemide is an antidepressant agent that reversibly inhibits the A-isozyme of the monoamine oxidaseenzyme system. In this study, single IV and oral doses were administered to a patient. A summary of the some of dataobtained from this experiment is given below.



Dose (mg) 150 100 100

AUC 2.58 1.70 1.52

AUMC 6.35 5.91 5.90

MRT (hr) 2.46 3.48 3.80

MAT (hr) 1.02 1.42

ke (hr-1) 0.406

ka (hr-1) 0.985 0.704

Cp0 1.05

Vd (L) 143

Cp at 1 hour 0.698 0.344 0.250

f .099 .088

Cpmax 1.05 .037 0.29 .079

Tmax (hr) 1.53 1.85 1.21



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



8.7.13 “NALBUPHINE” ON PAGE 73

Nalbuphine hydrochloride is an agonist-antagonist opiod which is used for its analgesic actions. In this study,volunteers were given single doses of four different nalbuphine forms. The data below focuses on a 10 mg iv dose anda 45 mg dose of an oral solution. A summary of the some of data obtained from this experiment is given below.



Dose (mg) 10 45 40 40

AUC 86.9 70.3 62.5 60

AUMC 288 306 280 270

MRT (hr) 3.31 4.35 4.48 4.5

MAT (hr) 1.04 1.17 1.19

ke (hr-1) .0301

ka (hr-1) 0.963 0.858 0.843

Cp0 26.2

Vd (L) 381

Cp at 1 hour 19.4 11.1 9.2 8.7

f 0.180 0.180 0.173

Cpmax 26.2 12.5 10.7 10.2 0.95

Tmax (hr) 1.76 1.88 1.90 1.01



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



8.7.14 “NEFAZODONE” ON PAGE 74

Shukla, U. et al., "Pharmacokinetics, absolute bioavailability, and disposition of nefazodone in the dog", Drug Metabolism and Disposition, Vol. 21, No. 3, (1993), p. 502 - 507.

Nefazodone was given to four healthy, adult, male beagles with an average weight of 11.0 kg. Each dog wasgiven a 10 mg/kg dose as a either a intravenous injection or as an oral solution or tablet. A summary of the some ofdata obtained from this experiment is given below.



Dose (mg/kg) 10 10 10 10

AUC 6023 829 800 700

AUMC 29283 4875 4800 4500

MRT (hr) 4.86 5.88 6.0 6.43

MAT (hr) 1.02 1.14 1.57

ke (hr-1) 0.210

ka (hr-1) 0.982 0.879 0.638

Cp0 1238

Vd (L) 8.07

Cp at 1 hour 1009 94.8 85.7 60.7

f 0.138 0.133 0.116

Cpmax 1238 112.7 105.6 84.0 0.80

Tmax (hr) 2.0 2.16 2.62 1.21



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



8.7.15 “ONDANSETRON” ON PAGE 75

Colthup, P., et al., "Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly", Journal of Phar-maceutical Sciences, Vol. 80, No. 9(1991), p. 868 - 871.

Ondansetron is a 5-hydroxyltryptamine compound which is useful in treating the nausea and vomiting which iscaused by the use of chemotherapy and radiation in the cancer patients. In order to determine the absolute bioavailabil-ity of oral Ondansetron, doses of 8 mg were given to two groups. One group received an oral dose and the other groupreceived an intravenous dose. A summary of the some of data obtained from this experiment is given below.



Dose (mg) 8 8 8

AUC 246.5 139 145

AUMC 1138 795 870

MRT (hr) 4.62 5.72 6.0

MAT (hr) 1.10 1.38

ke (hr-1) 0.217

ka (hr-1) 0.907 0.723

Cp0 53.4

Vd (L) 150

Cp at 1 hour 43 15.9 14.7

f 0.56 0.59

Cpmax 53.4 19.2 18.8

Tmax (hr) 2.1 2.4 1.1



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



8.7.16 “OMEPRAZOLE” ON PAGE 76

Anderson, T., et al, "Pharmacokinetics of various single intravenous and oral doses of omeprazole", Eur Journal of Clinical Phar-macology, 39, (1990), p. 195 - 197.

Omeprazole (mw: 345.42) is an agent which inhibits gastric acid secretion from the parietal cell. It is useful intreating such problems as ulcers and gastroesophageal reflux disease. One group received an iv bolus dose and theother group received an oral dose. A summary of the some of data obtained from this experiment is given below.



Dose (mg) 20 40 40

AUC 3.2 3.5 3.0

AUMC 3.2 5.25 4.5

MRT (hr) 1.0 1.5 1.5

MAT (hr) 0.5 0.5

ke (hr-1) 1

ka (hr-1) 2 2

Cp0 3.2

Vd (L) 52.4

Cp at 1 hour 1.18 1.63 1.40

f 0.55 0.47

Cpmax 3.2 1.8 1.5 0.86

Tmax (hr) 0.69 0.69 1



µmoleL

---------------- hr⋅

µmoleL

---------------- hr2⋅

µmoleL

----------------

µmoleL

----------------

µmoleL

----------------



8.7.17 “PAROXETINE” ON PAGE 77

Lund, J., et al., "Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man", Journal of Pharmacology and Toxicology, Vol. 51, (1982), p. 351 - 357.

Paroxetine kinetics and cardiovascular effects were studied in male subjects after single oral doses of 45 mgand slow intravenous infusion of 28 mg. A summary of the some of data obtained from this experiment is given below.



Dose (mg) 28 45 45

AUC 467 750 675

AUMC 6671 11250 10463

MRT (hr) 14.3 15 15.5

MAT (hr) 0.72 1.22

ke (hr-1) 0.07

ka (hr-1) 1.40 .082

Cp0 32.7

Vd (L) 856

Cp at 1 hour 30.5 37.9 25.5

f 1 0.90

Cpmax 32.7 44.8 37.6 0.84

Tmax (hr) 2.25 3.27 1.45



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



8.7.18 “RANITIDINE” ON PAGE 78

Garg, D., et al., "Pharmacokinetics of ranitidine in patients with renal failure", Journal of Clinical Pharmacology, Vol. 26 (1986), p. 286 - 291.

Ranitidine is an agent used in the treatment of peptic ulceration. In this study, ten patients with renal failurereceived either a 50 mg intravenous bolus dose or a 150 mg tablet. A summary of the some of data obtained from thisexperiment is given below.



Dose (mg) 50 150 150

AUC 5159 6422 6753

AUMC 53415 78752 84413

MRT (hr) 10.4 12.3 12.5

MAT (hr) 1.91 2.15

ke (hr-1) 0.0966

ka (hr-1) 0.524 0.466

Cp0 498

Vd (L) 100

Cp at 1 hour 452 240 231

f .0415 0.436

Cpmax 498 423 432 1.02

Tmax (hr) 3.96 4.26 1.07



ngmL-------- hr⋅

ngmL-------- hr

2⋅

ngmL--------

ngmL--------

ngmL--------



8.7.19 “SULPIRIDE” ON PAGE 79

Bressolle, F., Bres, J., and Faure-Jeantis, A., "Absolute bioavailability , rate of absorption, and dose proportionality of sulpiride in humans", Journal of Pharmaceutical Sciences ,Vol. 81, No. 1 (1992), p. 26 - 32.

Sulpiride is a substituted benzamine antipsychotic. In this study, the drug was administered to two groups.The first group received a 200 mg oral dose and the second group received a 100 mg intravenous infusion. A summaryof the some of data obtained from this experiment is given below.



Dose (mg) 100 200 200 200

AUC 8.27 8.79 8.6 8.0

AUMC 79.1 87.3 91.1 84.5

MRT (hr) 9.56 9.93 10.6 10.6

MAT (hr) 0.367 1.02 1.0

ke (hr-1) 0.865

ka (hr-1) 2.72 0.972 1.0

Cp0 0.865

Vd (L) 116

Cp at 1 hour 0.779 0.798 0.526 0.498

f 0.53 0.52 0.48

Cpmax 0.865 0.807 0.687 0.643 0.94

Tmax (hr) 1.24 2.57 2.52 0.98



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------



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141. Spalding, B.J., The Generic Industry: One Year Later, Am. Drug., 202(3):14- 16, 1990.

142. Loudin, A., Fallout From the Generic Drug Scandal, Pharm. Update, 2(5):1-9, 1991.

143. Pal, S. and D'Angelo, A.C., More Patient Questions, More Brand Name Rxs, U.S. Pharm., 15(3):66-70, 1990.



144. Consumer Confidence in Generic Drug Products Down in Wake of Industry Scandal, But Satisfaction withProducts Remains High, Survey Reveals, A.J.H.P., 47:468, 1990.

145. Pal, S. and D'Angelo, A.C., FDA Reputation Suffers, Pharmacists Ask for More Product Information, U.S.Pharm., 15(4):20-25, 1990.

146. Gross, L.H., Can Pharmacists, Physicians, and the Public Trust Generics? Am. Druggist, 200(3):25-28, 1989.

147. Most Generics are Safe, But Approval Process Remains in 'Disrepair', Am. Pharm., NS30(1):14, 1990.

148. Conlan, M.F., Getting it Back on Track, Drug Topics, 134(3):42-47, 1990.

149. Cardinale, V., Generics: Where Now? Drug Topics (Supplement):3S, 1993.

150. Conlan, M.F., Future is Sunny for Generics as Popular Rxs Come Off Patent, Drug Topics, 134 (20):14-19,1990.

151. Starr, C., Which Drugs Are Going Off Patent or Losing Exclusivity?, Drug Topics (Supplement):14S-15S,1993.

152. Summers, K.H., Counseling Patients Who Take Generic Drug Products, Drug Topics (Supplement):45S-54S,1993.

153. Laskoski, G., Generics: Too Good For Their Own Good, Am. Druggist, 208(3):30-35, 1993.

154. Shafermeyer, K.W., Schondelmeyer, S.W., and Wilson, G.T., The FDA Orange Book: Expectations VersusRealities, J. Pharm. and Law, 1:13-26, 1992.

155. Chappell, S.C., Pharmacists Now Control 27% of Dispensing Decisions Involving New Rxs, Pharm. Times,54(10):55-62, 1988.

156. Simonsen, L., Rx Dispensing Trends: Pharmacists Make More Selection Decisions, Pharm. Times,57(10):53-59, 1991.

157. Simonsen, L., Rx Brand Choice: Pharmacists Decide for 35% of All New Rxs, Pharm. Times, 58(10):92-98,1992.

158. Simonsen, L., Generic Prescribing and RPh Substitution Continue to Climb, Pharm. Times, 59(10):29-30,1993.

159. D'Angelo, A.C., How To Win Pharmacists and Influence Purchasing, U.S. Pharm., 16(6):35-36, 1991.

160. Charupatanapong, N. and Rascati, K.L., Pharmacists' Satisfaction With Drug Product Selection Legislation,Am. Pharm., NS28(10):27-32, 1988.

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162. Segal, R., Wantz, D.L. and Brusadin, R.A., Pharmacists' Decision Making in the Selection of Generic Pharma-ceuticals, J. Pharm. Market. Mngment., 4(1):75-91, 1989.

163. McCormack, J.P., Levine, M. and Miller, P., Bioequivalence: Just the Facts Please, CPJ-RPC, Sep:404-407,1990.

164. Guidelines for Pharmacists Performing Product Selection, Pharm. Today, Feb. 2:4-5, 1990.

165. Gagnon, J.P., Key Factors and Cues for Evaluating Pharmaceutical Manufacturers, Pharm. Times, 56(4):45-48,1990.



166. Feinberg, J.L., A Pharmacist's Survival Guide to the Generic Drug Scandal, Consult. Pharm., 5(1):15-23,1990.

167. Foster, T.S., Selecting Therapeutically Equivalent Products: Special Cases, Am. Pharm., NS31(11):49-54,1991.

168. Ross, M.B., Status of Generic Substitution: Problematic Drug Classes Reviewed, Hosp. Formul., 24:441-449,1989.

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170. Ansbacher, R., Conjugated Estrogens: Do Not Substitute, Am. Pharm., NS30(7):27-28, 1990.

171. Locniskar, A., Greenblatt, D.J., Harmatz, J.S., and Shader, R.I., Bioinequivalence of a Generic Brand of Diaz-epam, Biopharm. Drug Disp., 10:597-605, 1989.

172. Rentmeester, T.W., Doelman, J.C., and Hulsman, J.A.R.J., Carbamazepine: Merkpreparaat en Generiek,Pharm. Weekbl., 125(43):1108-1110, 1990.

173. Welty, T.E., Pickering, P.R., Hale, B.C. and Arazi, R., Loss of Seizure Control With Generic Substitution ofCarbamazepine, Annals Pharmacotherapy, 26:775-776, 1992.

174. Grubb, B.P., Recurrence of Ventricular Tachycardia After Conversion From Proprietary to Generic Procaina-mide, Am. J. Cardiol., 63:1532-1533, 1989.

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BASIC PHARMACOKINETICS - CHAPTER 8: Bioavailability