Biopharmaceutics and Pharmacokinetics

Ivan N. Tanodra, MD, RPh

Bio=Pharmaceutics

Lifegeneral area of study general area of study concerned with the concerned with the formulation, formulation, manufacture, stability manufacture, stability and effectiveness of and effectiveness of pharmaceutical dosage pharmaceutical dosage formsforms

Biopharmaceutics

• study of the factors influencing the bioavailability of a drug in man and animals and the use of this information to optimize pharmacological or therapeutic activity of drug products in clinical application

Biopharmaceutics

• Interrelationship of the physicochemical properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of drug absorption

Biopharmaceutics

• Study of the relationship of the physicochemical properties and in vitro behavior of the drug & drug product on the delivery of the drug to the body under normal or pathologic conditions

•PHARMACOKINETICS – a process of how the body deals with the drug, “what your body does to your drug”

•PHARMACODYNAMICS – a process of how your drug deals with the body, “what your drug does to your body”

Pharmacokinetics

• Deals with the changes of drug concentration in a drug product inside the human or animal body following administration

Pharmacokinetics

• Involves the kinetics of drug absorption, distribution, metabolism and elimination

Pharmacodynamics

• Relationship between the drug concentration at the site of action (receptor) and pharmacologic response

Drug Product

• Finished dosage form that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredient (vehicle)

• Formulation or matrix in which the drug is contained

• Term may also include a dosage form that does not contain an active ingredient intended to be used = placebo

Physicochemical properties of drug product

Pharmacologic/clinical effect

Rationale

• Apply biopharmaceutic principles in developing a rational design of a drug product which would enhance the delivery of active drug and provide optimal therapeutic efficacy of the drug in the patient

AIM:

To deliver the right amount of drug that is EFFECTIVEand SAFE at the right place (site of action) and at the right time (oral, SL or IV/ fast or slow-release)

• Mometasone cream AND Mometasone (Nasonex) nasal spray

• Methylprednisolone tablet AND Fluticasone spray• Salbutamol nebules, Salbutamol MDI and

Salbutamol syrup• Nitroglycerin patch AND Nitroglycerin spray• Lactacyd facial wash AND Lactacyd feminine wash• Atropine eyedrops AND Atropine ampule• Lidocaine spray, Epinephrine ampule and

Lidocaine:Epinephrine carpule

Let us now focus on drugs intended for systemic use….

Let’s discuss the disposition of a drug

DOSAGE FORMROUTE OF ADMINISTRATION

Bioavailability of the drug (active ingredient) is the primary concern of biopharmaceutics- Remember you AIM

How do you measure the bioavailability of a drug?

1. Blood = plasma level concentration2. Urine3. Feces – reflect a drug that has not been

absorbed after an oral dose or a drug that has been biliary secreted after systemic absorption

4. Clinical outcome/Pharmacologic effect/pharmacodynamic effect

Which is the most direct measurement?

Plasma Level – Time Curve

Time (mins.)

Plasma level (mg/mL)

Identify….

• Peak plasma level (cmax)– max drug concentration related to the dose & the rate constants for absorption & elimination of the drug

• AUC (Area Under the Curve)- related to the amount of drug absorbed systemically

• Time of peak plasma level (tmax)– time of max drug conc. in plasma roughly proportional to the average rate of drug absorption

Determine the route of administration

• IV• Oral

Higher plasma level concentration = ___________? bioavailability

Establish

• Minimum effective concentration (MEC)• Minimum toxic concentration (MTC)

You will be able to determine….

•Onset time of action•Duration of action• Intensity of drug actio

•--Through the plasma level time curve

Most of the time……..

Plasma level concentration of a drug = concentration of drug at the receptor sites = intensity of a pharmacologic effect

Is measuring plasma concentrations of a drug enough

to determine its therapeutic efficacy?

Pharmacodynamic Response

•Digoxin = ECG tracings•Warfarin = Prothrombin time• Insulin = Blood glucose levels•Simvastatin = Blood cholesterol levels•Nifedipine (anti-hypertensive) =

___________________•Paracetamol = ___________________

Plasma drug concentrations do not accurately predict pharmacodynamic response

Action of warfarin is dependent on the clotting factors II, VII, IX & X

Having the same trend of plasma level concentration of Warfarin…..

• Will the intensity of the activity of Warfarin in a hemophiliac be the same with a normal person?

IQ

A 64 year-old male, diabetic patient with a poor creatinine clearance is being given Gentamycin 80mg (aminoglyocside) IV once daily as a treatment for sepsis. Which is important:

a.Blood culture and sensitivity to determine his response to treatment

b.Plasma level concentration to determine the blood level of the drug

c.A and B

Why?

Pharmacokinetic Models

• Drugs are in a dynamic state within the body

• It is a hypothesis conceived using mathematical terms

• Describe drug concentrations in the body as a function of unit time

Pharmacokinetic Models

Concentration of drug in the tank would be governed by two parameters which are CONSTANT:

1.Fluid volume of the tank2.Elimination of drug per unit of time

Let us correlate the LADMER System with Pharmacokinetic Models

Pharmacokinetic Models

If a known set of drug concentrations in the tank were determined at various intervals à volume of fluid in the tank & rate of drug elimination would be established

Pharmacokinetic Models

• A compartment is a tank containing a volume of fluid

• In the human body, a fraction of drug is continually eliminated as a function of time

Pharmacokinetic Models

•Concentration of drug in the tank (compartment) after a given dose (Ab) is governed by two parameters:1. Fluid volume of the tank (Vd)2. Elimination of drug per unit of time (kel, CL)

à this could be established by knowing a set of drug concentrations in the tank (Cp) at various time intervals

Pharmacokinetic Models

•The number of parameters needed to describe the model depends on:1. Complexity of the process (ADME)2. route of drug administration

Uses of Pharmacokinetic Models

• Predict plasma, tissue and urine drug levels with any dosage regimen

• Calculate the optimum dosage regimen for each patient individually

• Estimate possible accumulation of drug and/or metabolites

• Correlate drug concentrations with pharmacologic or toxicologic activity

Uses of Pharmacokinetic Models

• Evaluate differences in the rate or extent of availability between formulations (bioequivalence)

• Describe how changes in physiology or disease affect the absorption, distribution and elimination of the drug

• Explain drug interactions

Pharmacokinetic Models

A.Compartment Model (Mammillary Model) B.Physiologic Pharmacokinetic Model (Flow

Model)

Compartment (Mammillary) Model

• One or more peripheral compartment connected to a central compartment like satellites

• DRUG IN THE BODY = CENTRAL COMPARTMENT + TISSUE COMPARTMENT

Compartment (Mammillary) Model

Compartment is not a real physiologic or anatomic region

Used when there is little information known about the tissues

ASSUMPTION: Compartment à group of tissues that have a similar blood flow and drug affinity

Within each compartment, drug is uniformly distributed

OPEN – drugs move in & out of the compartment (dynamic)

Compartment (Mammillary) Model

ASSUMPTION:•Drug has an equal probability of leaving the compartment

Compartment Models

• Rate constants (ka & ke) represents the overall rate processes of drug entry into and exit from the compartments

Compartment Model

FUNCTIONS:•Enables the pharmacokineticist to write

different equations to drug concentration changes inside each compartment

•Visual representation of rate processes•Shows how many pharmacokinetic

constants are necessary to describe the process adequately

Compartment Models

•Open-one compartment model•Open-two compartment model

•Compartment model for IV and oral

Compartment Model

• Can a drug concentration data be obtained directly from each compartment???

• In open two compartment à data in the peripheral compartment cannot be obtained à tissues are not easily sampled & may not contain homogenous concentration of the drug à only estimated mathematically (from amount of drug absorbed & eliminated per unit time)

Compartment Model

DISADVANTAGES:•NOT REALISTIC because everything is

based on presumption and mathematical concept•à Cannot be extrapolated to humans

Physiologic Pharmacokinetic Model

• Blood flow or perfusion model• Based on known anatomic and physiologic data

à MORE REALISTIC• Actual tissue volume is used• Experimentally determined in ANIMALS à

extrapolated to humans• No data fitting required• On model à if there’s no perfusion, organ is

excluded (e.g. brain)

Construct the model….

• IV injection, Venous blood, Arterial blood, Heart, Muscle, Slowly equilibrating tissue (SET), Rapidly equilibrating tissue (RET), Kidney, Liver, ke, km, Perfusion (Q) Qh, Qm, Qs, Qr, Qk, Ql, Urine

Physiologic Pharmacokinetic Model

• DISADVANTAGE: 1.Data can be experimentally difficult to

obtain2.Data can be affected by pathophysiologic

conditions

Factors Affecting Design of a Drug Product

DRUG•Dosage form•Dose (mg/kg)•Physicochemical

properties•Route of administration

BODY•Physiologic factors

(e.g. age, body mass)•Pathologic factors (e.g.

liver and renal disease)

Application of Biopharmaceutics

• Generic equivalency• Drug availability• Therapeutic efficacy• Drug substitution