Bioequivalence stuides

2. There are several formulations of the
same drug, in the same dose, in a
dosage form and meant for to be given
by the same route. In order to ensure
clinical performance of such drug
products, bioequivalence studies
should be performed.
The following are the terms relevant in
this context.

3. Equivalence:
Equivalence is a comparative term, which presumes that
one drug product, is similar with respect to a specific
characteristic or function to another, or to the defined set
of standards.
Chemical equivalence:
It indicates that two or more drug products contain the
same labeled chemical substance as an active ingredient
in the same amount.
Pharmaceutical equivalence:
This term implies that two or more drug products are
identical in strength, quality, purity, content uni9formity,
dissolution and disintegration characteristics.

4. Bioequivalence:
It is relative term which denotes that the
drug substance in two or more identical dosage
forms, reaches the systemic circulation at the
same relative rate and to the same relative
extent.
Therapeutic equivalence:
This term indicates that two or more drug
products that contain the same therapeutically
active ingredient, elicit identical
pharmacological effects and can control the
disease to the same extent.

5. BIOEQUIVALENCE STUDY INVOLVES
CONSIDERATION OF THE FOLLOWING
FACTORS:
 DRUG: We compare the drug products with
the same drug in each dosage form.
 SUBJECTS: A number of factor such as
health, age, weight, enzyme status and
number are concern.
 HEALTH: The subjects should be of good
health.
 AGE: subject between the ages of 18-35
years are preferred.

6. WEIGHT: Subjects, normal weights are
preferred.
ENZYME STATUS: Altered kinetic for
the drugs in cases of smokers or
subject taking other drugs
NUMBER: The number of subjects
included in the study is sufficient to see
the real difference in the bioavailability
(about 20% variation).

7. The in vivo bioequivalence study requires
determination of relative bioavailability
after administration of a single dose of test
and reference formulations by the same
route, in equal doses, but at different
times. The study is performed in fasting,
young, adult male volunteers to assure
homogeneity in the population.
Homogeneity in study population permits
focus on formulation factors.

8. The volunteers are used in complete, open
label cross over fashion such as the Latin
Square cross over design.
In Latin square cross over design each
formulation is administered once to each
subject and once in each study period and
unlike parallel design, all the subjects do
not receive the same formulation at the
same time.

9. US Food and Drug Administration :
Has imposed guidelines on bioequivalence on the
basis of the following:
 Availability of multiple brands of the same compound
each with claims for the perfect bioavailability.
 Various drug products do not give comparable
therapeutic effect as seen from well controlled
clinical trials.
 It is especially important for drugs that have a narrow
therapeutic index.

10.  Lack of bioequivalence will have a serious
adverse effect in the treatment of a serious
disease.
 Evidence that the various physicochemical
properties of the drug, pharmaceutical
excipients used and the method of
manufacturing have a significant effect on
bioavailability.
 Evaluation of a range of generic products
indicated that some of the products were not
equivalent with the brand leader.

11. Types of bioequivalence
requirement
The types of bioequivalence requirements 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.

12. Subjects selection for Bioequivalence
study
 Young Healthy, persons in the Age
group of 18-40. With ideal body
weight(10%).
 Free of medical problems.
 Not using any medicines currently.
 Pregnant and nursing females are
excluded.

13. Cross-over study
Most common preferred method for
determining generic bioequivalence
 Latin square cross over design
 Single dose cross over study
 Two way cross over study
 Three way cross over
 Four way cross over
 Parallel studies
 Steady state studies

14. Subject number Study period 1 Study period 2 Study period 3
1 X Y Z
2 Y Z X
3 Z X Y
4 X Z Y
5 Z Y X
6 Y X Z

15. Advantages of Cross-over Studies
It minimizes the intersubjects variability in
plasma drug levels.
Minimizes the carryover effects which
could occur when a given dosage form
influences the given bioavailability of a
subsequently administered product.
Minimizes the variation due to tome effect.
Makes it possible to focus more on
formulation variables which is the key to
success for any bioequivalence studies.

16. A draw back of such a cross-over design is
that the study takes a long time since an
appropriate washout period between two
administrations is essential which may be
very long if the drug has a long half life.
When the number of formulations to be
tested are more, the study becomes more
difficult and subject dropouts are also high.

17. Statistical interpretation of bioequivalence
data:
 An analysis of variance type of statistical method is
used to determine statistical differences.
 A statistically significant difference of 10 % in the
extent of absorption between the two formulations is
insignificant clinically.
 Currently, a simple rule is that if the relative
bioavailability of the test formulation is in the range
of 80-120 % of reference standard, it is considered
bioequivalent.
 The difference between the bioavailabilities of the
test formulations should not be greater than +/- 20%
of hte average of reference standard.

18. References
1. Biopharmaceutics & Pharmacokinetics. A
Treatise by D.M.Brahmankar & Sunil
B.Jaiswal.
2. Textbook of Biopharmaceutics &
Pharmacokinetics by Dr.Shobha Rani R.
3. Fundamentals of Biopharmaceutics &
Pharmacokinetics by V.Venkateswarlu.