Parameters to evaluate Bioequivalence

1. Presented by:
Vinitha Nair
M.Sc Bio-analytical Sciences
Part 2

2. Contents
• Bioequivalence
• Bioequivalence: Background
• Goals of BE
• Pharmaceutical Equivalents
• Pharmaceutical Equivalence
• Pharmaceutical Alternatives
• Therapeutic Equivalence
• Interchangeable Pharmaceutical Products
• Parameters
• Concept of “Half Life”
• References

3. Bioequivalence
Two medicinal products are bioequivalents if they are
pharmaceutical equivalents or alternatives and if their
bioavailabilities (rate and extent) after administration
in the same molar dose are similar to such degree that
their effects, with respect to both efficacy and
safety, will be essential the same.

5. Bioequivalence: Background
1
• Using bioequivalence as the basis was established by the
“Drug Price Competition and Patent Term Restoration Act of
1984,” also known as the Waxman-Hatch Act.
2
• This Act permits FDA to approve applications to market
generic versions of brand-name drugs without conducting
costly and duplicative clinical trials.
3
• At the same time, the brand-name companies can apply for
up to five additional years longer patent protection for the
new medicines they developed.
4
• Brand-name drugs are subject to the same bioequivalence
tests as generics upon reformulation.

6. Goals of BE
Bioequivalence
studies focus
on changes to
the dosage
form process
after pivotal
studies
commence to
ensure
product on
the market is
comparable to
that upon
which the
efficacy is
based.
Establish that a new formulation has
therapeutic equivalence in the rate and
extent of absorption to the reference
drug product.
Important for linking the commercial drug
product to clinical trial material at time of
NDA.
Important for post-approval changes in
the marketed drug formulation.

7. 7
Pharmaceutical Equivalents
• Contain the same amount of the same active substance in the
same dosage form.
• Meet the same or comparable standards.
• Intended to be administered by the same route.
Pharmaceutical equivalence by itself does not
necessarily imply therapeutic equivalence

8. Pharmaceutical Equivalence
Reference Test
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence
(Note: Generally, same dissolution specifications)

9. Pharmaceutical Alternatives
 identical therapeutic moiety, or its precursor not
necessarily the same:
• salt or ester of the therapeutic moiety
• amount
• dosage form

10. Therapeutic Equivalence
• Pharmaceutically equivalent
• Their effects, with respect to both
efficacy and safety, will be
essentially the same as derived
from appropriate studies
Clinical
studies &
In vitro
studies
Pharmaco
dynamic
studies
Bio
equivalnce
studies

11. Interchangeable Pharmaceutical
Products
If a product is demonstrated to be
therapeutically equivalent to a reference
product, then the products are considered
interchangeable.

12. Concept of interchangeability includes the
equivalence of the dosage form as well as for the
indications and instructions for use.
Therapeutic equivalence of a multiscource
product can be assured when the multiscource
product is both pharmaceutically
equivalent/alternative and bioequivalent.
TE = PE + BE

13. Parameters
These are following parameters:

14. • AUC: area under the concentration-time curve measure of the
extent of bioavailability
• Cmax: the observed maximum concentration of drug measure of
both the rate of absorption and the extent of bioavailability (µg/mL or
ng/mL)
• Tmax: the time after administration of drug at which Cmax is observed
measure of the rate of absorption (minutes or hours)
Note that bioequivalence standards are applied to the pharmacokinetic parameters
AUC and Cmax but not to Tmax.

15. • Pharmacokinetic Studies
Key Measurements
• AUC
– Area under the concentration-
time curve
• Cmax
– Maximum concentration
– A difference of greater than 20%
in Cmax or the AUC represents a
significant difference between the
test and reference compounds
• Tmax
– Time to maximum concentration
Test Compound
Reference Compound
Time(Hr)
Plasma
Concentration(µgml)
Cmax
Tmax
AUC
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16. To establish BE:
 The calculated 90% CI for Cmax & AUC, should fall within range:
80-125% (Range of Bioequivalence)
 Non-parametric data 90% CI for Tmax should lie within
clinical acceptable range

17. Concept of “Half Life”
 ½ life = how much time it takes for blood levels of drug to decrease
to half of what it was at equilibrium
 There are really two kinds of ½ life…
 “distribution” ½ life = when plasma levels fall to half what they
were at equilibrium due to distribution to/storage in body’s
tissue reservoirs
 “elimination” ½ life = when plasma levels fall to half what they
were at equilibrium due to drug being metabolized and
eliminated
 It is usually the elimination ½ life that is used to determine dosing
schedules, to decide when it is safe to put patients on a new drug

18. References
 www.authorstream.com/.../sanketrekhawar111-466277-bioequivalence
 www.thaifda.com/editor/data/files/.../BABE_concept
 www.icmcc.org/ppt/roy.ppt
 www.powershow.com
 www.fda.gov/ohrms/dockets/ac/04/slides/4034S2_12_Lionberger.ppt
 www.fda.gov/ohrms/dockets/ac/04/slides/4034S2_07_Haidar.ppt