Pharmacokinetics: Lecture Five

Anas Bahnassi PhD RPh

Bioavailability and Bioequivalence

Lecture Objectives

Upon the completion of this lecture the student should be able to:

• Define terms bioavailability, absolute bioavailability, comparative bioavailability,

bioequivalence, therapeutic equivalence, pharmaceutically equivalent products and

pharmaceutical alternatives

• Explain the difference between bioequivalence and therapeutic equivalence and

describe whether bioequivalence will, in all cases, lead to therapeutic equivalence

• Calculate absolute and relative bioavailability

• Explain the manner in which parameters reflecting rate and extent of absorption are

used to determine bioequivalence between two formulations; use equations to

calculate these parameters

• Explain the first-pass effect and its influence on bioavailability of a drug

• Perform calculations to assess bioequivalency by the method employed by the US

Food and Drug Administration (FDA)

• Explain the FDA rating system for bioequivalency.

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Bioavailability

Definitions

The relative amount of an administered dose that reaches the general circulation and the rate at

which this occurs

The rate and extent to which the active ingredient or therapeutic moiety is

absorbed from a product and becomes available at the site of drug action

Pharmaceutical or Chemical Equivalence


Means that two or more drug products contain equal amounts of the same therapeutically active ingredients in

identical dosage forms, and that these dosage

forms meet the requirements such as

purity, content uniformity and disintegration time as established by the United

States Pharmacopeia and/or National

Formulary.

Therapeutic Equivalence

Two or more chemically or pharmaceutically

equivalent products essentially

produce the same efficacy and/or toxicity in the same

individuals when administered in an

identical dosage

regimen.

Two or more chemically or pharmaceutically equivalent products

produce comparable bioavailability characteristics in any individual when

administered in equivalent dosage regimen (parameters compared include the area

under the plasma concentration versus time curve (AUC) from time zero to infinity AUC ,

maximum plasma concentration and the time of peak concentration).


Bioequivalence Compare

Bioequivalence and

Therapeutic Equivalence


Bioavailability

Absolute

Comparing AUC or total Xu of extravascular administration to

intravascular administration

Relative

Comparing bioavailability parameters derived from plasma or urine data

between two different dosage forms or two different extravascular routes of

administration


im


Absolute

Bioavailability

F=

(𝑨𝑼𝑪)𝒆𝒙𝒕𝒓𝒂𝒗𝒂𝒔𝒄𝒖𝒍𝒂𝒓𝑫𝒐𝒔𝒆𝒆𝒙𝒕𝒓𝒂𝒗𝒂𝒔𝒄𝒖𝒍𝒂𝒓

(𝑨𝑼𝑪)𝒊𝒗𝑫𝒐𝒔𝒆𝒊𝒗

F=(𝑨𝑼𝑪)𝒐𝒓𝒂𝒍

(𝑨𝑼𝑪)𝒊𝒗×

𝑫𝒐𝒔𝒆𝒊𝒗

𝑫𝒐𝒔𝒆𝒐𝒓𝒂𝒍

F=

(𝒙𝒖)𝒆𝒙𝒕𝒓𝒂𝒗𝒂𝒔𝒄𝒖𝒍𝒂𝒓𝑫𝒐𝒔𝒆𝒆𝒙𝒕𝒓𝒂𝒗𝒂𝒔𝒄𝒖𝒍𝒂𝒓

(𝒙𝒖)𝒊𝒗𝑫𝒐𝒔𝒆𝒊𝒗

F=(𝒙𝒖)𝒐𝒓𝒂𝒍

(𝒙𝒖)𝒊𝒗×

𝑫𝒐𝒔𝒆𝒊𝒗

𝑫𝒐𝒔𝒆𝒐𝒓𝒂𝒍


Relative

Bioavailability

F=(𝑨𝑼𝑪)𝒐𝒓𝒂𝒍

(𝑨𝑼𝑪)𝒊𝒎×𝑫𝒐𝒔𝒆𝒊𝒎

𝑫𝒐𝒔𝒆𝒐𝒓𝒂𝒍 F=

(𝒙𝒖)𝒕𝒂𝒃𝒍𝒆𝒕

(𝒙𝒖)𝒔𝒐𝒍𝒖𝒕𝒊𝒐𝒏×𝑫𝒐𝒔𝒆𝒔𝒐𝒍𝒖𝒕𝒊𝒐𝒏

𝑫𝒐𝒔𝒆𝒕𝒂𝒃𝒍𝒆𝒕


Bioequivalence

A type of relative bioavailability

F=(𝑨𝑼𝑪)𝒈𝒆𝒏𝒆𝒓𝒊𝒄

(𝑨𝑼𝑪)𝒔𝒕𝒂𝒏𝒅𝒂𝒓𝒅×𝑫𝒐𝒔𝒆𝒔𝒕𝒂𝒏𝒅𝒂𝒓𝒅

𝑫𝒐𝒔𝒆𝒈𝒆𝒏𝒆𝒓𝒊𝒄

We compare an innovative product (standard) with generic product


Factors affecting Bioavailability

Formulation Factors

Excipients

Particle size

Crystalline or amorphous

Hydrous or anhydrous

Physiological Factors

Gastric emptying

Intestinal motility

GIT pH changes

Changes in intestinal wall

The First Pass Effect


The fraction, f, of orally administered drug that successfully passes through gut lumen and gut wall is

then taken via the hepatic portal vein to the liver, where metabolism of the drug by enzymes may take

place. This extraction by the liver of orally administered drug

is called the first pass effect.

Determination of the area under the plasma concentration–time curve from

intravenous bolus administration


𝐶𝑝 =𝑥0𝑉𝑒−𝑘𝑡 𝐴𝑈𝐶 = 𝐶𝑝. 𝑑𝑡

∞

0

𝐴𝑈𝐶 = 𝐶𝑝. 𝑑𝑡

∞

0

=𝑥0𝑉 𝑒−𝑘𝑡∞

0

. 𝑑𝑡 = −𝑥0𝑉𝑘

𝑒−𝑘𝑡∞ − 𝑒−𝑘𝑡0


∞

0

=𝑥0𝑉𝑘=𝐷𝑜𝑠𝑒

𝐶𝑙=𝐹𝑥0𝐶𝑙

Extra-vascular

Determination of the area under the plasma concentration–time curve from

extravascular administration



∞

0

=𝑘𝑎𝐹𝑥0

𝑉(𝑘𝑎 − 𝑘)𝑒−𝑘𝑡 − 𝑒−𝑘𝑎𝑡 . 𝑑𝑡


∞

0

𝐶𝑝𝑡 =𝑘𝑎𝐹𝑥0

𝑉(𝑘𝑎 − 𝑘)𝑒−𝑘𝑡 − 𝑒−𝑘𝑎𝑡

𝐴𝑈𝐶 =𝑘𝑎𝐹𝑥0

𝑉(𝑘𝑎 − 𝑘)𝑒−𝑘𝑡 − 𝑒−𝑘𝑎𝑡 𝑜∞

𝐴𝑈𝐶 =𝑘𝑎𝐹𝑥0

𝑉(𝑘𝑎 − 𝑘)𝑘𝑎 − 𝑘𝑘𝑘𝑎

=𝐹𝑥0𝑉𝑘

=(𝑥𝑢)0𝐶𝑙


Assessing Rate of Absorption means

comparing:

Peak Time (tmax) Peak

Concentration (Cmax)

tmax

Cmax

Bioavailability Testing


Administer Drug to Healthy Individuals, Analyze Plasma and

Urine Samples

For Relative Bioavailability Apply

Crossover Design

Minimum 12 Subjects

Normally 18-24

Informed Conscent

Medical Check up

Laboratory Testing

Fast Volunteers Overnight


Bioavailability Testing

1. Check the criteria for bioavailability testing. 2. Compare bioavailability parameters for products 3. being tested: AUC, peak plasma concentration, peak time

and/or amount of drug excreted in urine (Xu). 4. Examine the information provided for statistical analysis. 5. Determine the percentage differences for each parameter

between products being tested. 6. Apply the 20% rule as a rough indicator in the absence of

statistical analysis. 7. Know the use of the drug being tested: is onset of action

more important or duration? What is the therapeutic range? Is it narrow or broad?

Example


12 Subjects

250mg of Generic Drug

250mg of Brand Drug

Randomly Assigned to 2 groups (6/6)


𝑨𝑼𝑪𝒈𝒆𝒏𝒆𝒓𝒊𝒄 = 𝟑𝟏. 𝟔𝟎 𝑨𝑼𝑪𝑩𝒓𝒂𝒏𝒅 = 𝟑𝟒.79

𝑨𝑼𝑪𝒈𝒆𝒏𝒆𝒓𝒊𝒄

𝑨𝑼𝑪𝑩𝒓𝒂𝒏𝒅= 0.9083 Is it

acceptable?

Data Presentation


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Data Presentation

How Equivalence Types are Determined

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Same Drug

Not Equivalent

Same Amount of Active Ingredient in

identical dosage form

Pharmaceutical Alternative

Significant difference in

rate or extent of Absorption

Pharmaceutical Equivalent

Bioinequivalent

Bioequivalent

Therapeutic Equivalent

Yes

Yes

Yes Yes

Should Result in

No

No

FDA Codes of Bioequivalence

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Fallacies


If a drug product passes official USP or BNF standards then this assures

bioavailability in humans.

If drug products containing the same active ingredient(s) do have different bioavailabilities and/or different therapeutic differences,

then this will be recognized in clinical use of the drug and

reported in the scientific literature.

Bioavailability must always be related to pharmacological effects or clinical

response.

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Fallacies

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In vitro rate of dissolution tests can disclose differences in

bioavailability and/or therapeutic effects

without parallel data on the same drug products

in human.

Differences in bioavailability

From one manufacturer’s product to the next are less important

than differences between the labeled dose and average

potency as determined by chemical assay in vitro or in vivo

in an animal system.

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Pharmacokinetics

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Pharmacokinetics: Lecture Five