2. 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
Anas Bahnassi PhD 2011
• 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.
2
3. Bioavailability
Definitions
The relative amount of an The rate and extent to which the active
administered dose that reaches the ingredient or therapeutic moiety is
general circulation and the rate at absorbed from a product and becomes
which this occurs available at the site of drug action
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4. Pharmaceutical
Therapeutic
or Chemical
Equivalence
Equivalence
Means that two or more Two or
drug products contain more chemically or
equal amounts of the pharmaceutically
same therapeutically
equivalent
active ingredients in
identical dosage forms,
products essentially
and that these dosage produce the same efficacy
forms meet the and/or toxicity in the same
requirements such as individuals when
purity, content uniformity administered in an
and disintegration time as identical
established by the United dosage
States Pharmacopeia regimen.
and/or National
Formulary.
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5. Bioequivalence
Compare
Bioequivalence
and
Two or more chemically or Therapeutic
pharmaceutically equivalent products Equivalence
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).
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6. Bioavailability
Absolute Relative
Comparing bioavailability parameters
derived from plasma or urine data
between two different dosage forms or
Comparing AUC or total Xu of two different extravascular routes of
extravascular administration to administration
intravascular administration
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10. (������������������)������������������������������������������ ������������������������������������������������������������������������
F= ×
(������������������)������������������������������������������������ ������������������������������������������������������������������
A type of relative
bioavailability
Bioequivalence
We compare an innovative product
(standard) with generic product
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11. Excipients
Particle size
Formulation
Factors
Crystalline or
amorphous
Hydrous or
anhydrous
Factors affecting
Bioavailability Gastric
emptying
Intestinal
motility
Physiological
Factors
GIT pH
changes
Changes in
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intestinal wall 11
12. 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.
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16. Bioavailability Testing
Administer Drug to Minimum 12
For Relative
Healthy Individuals, Subjects
Bioavailability Apply
Analyze Plasma and
Crossover Design Normally 18-24
Urine Samples
Informed Conscent
Fast Volunteers
Medical Check up
Overnight
Laboratory Testing
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17. 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?
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18. Example
12 Subjects
Randomly
Assigned to 2
groups (6/6)
250mg of 250mg of Brand
Generic Drug Drug
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19. ������������������������������������������������������������ = ������������. ������������ ������������������������������������������������ = ������������.79
������������������������������������������������������������ Is it
= 0.9083
������������������������������������������������ Anas Bahnassi PhD 2011
acceptable? 19
22. How Equivalence Types are
No
Same Drug
Not
Determined
Yes Equivalent
Therapeutic
Same Amount of
Equivalent
Active Ingredient in No Pharmaceutical
identical dosage Alternative
form Should
Result in
Yes
Yes Significant Yes
Bioequivalent
Pharmaceutical difference in
Equivalent rate or extent
of Absorption
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Bioinequivalent
22
24. 1
If a drug product passes official USP or Fallacies
BNF standards then this assures
bioavailability in humans.
2 Bioavailability must always be related
to pharmacological effects or clinical
response.
If drug products containing the
same active ingredient(s) do have
3
different bioavailabilities and/or
different therapeutic differences,
then this will be recognized in
clinical use of the drug and
reported in the scientific
literature.
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25. In vitro rate of dissolution tests
Fallacies
4
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
5
than differences between the
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labeled dose and average
potency as determined
by chemical assay
in vitro or in vivo
in an animal
system. 25