Bioavailability bioequivalence study

1. Bioavailability / Bioequivalence
Studies
Presented by:-
Miss. Malusare Anita
M.Pharm sem.-1
Dept. of P. Chemistry
Guided by:-
Prof.-Uttekar P. S.
P.E. Society’s Modern College of Pharmacy Nigdi,Pune-44
1

2. Overview
 Introduction
 Need Of Studies
 Definitions
 Concept Of Equivalent
 Measurement Of Bioavailability
 Bioequivalence Studies
Basic Design Considerations
 References
2

3. Introduction
 BA & BE are Essential to ensure uniformity in standards
of quality, efficacy & safety of Pharmaceutical
products.
 Release of an active substance should be known &
reproducible.
 Both Bioavailability & Bioequivalence focus on release
of drug substance from its dosage form & subsequent
absorption in circulation.
3

4. Why are bioavailability And
bioequivalence studies
necessary?
4

5. Background
 First Product to Market
 Other products with same medicinal
ingredient
 Pharmaceutical equivalence
5

6. Bioavailability
 Measurement of the relative amount & rate at which,the drug
from administered dosage form, reaches the systemic
circulation & becomes available at the site of action.
 Bioavailable fraction (F), refers to the fraction of
administered dose that enters the systemic circulation
 F = Bioavailable dose
Administered dose
Reference:
Intravenous administration = 100% bioavailability 6

7. Important Pharmacokinetic
Parameters
 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
 tmax: the time after administration of drug at which Cmax
is observed  measure of the rate of absorption
7

8. Absolute Bioavailability
 Compares the bioavailability of the active drug in systemic
circulation following non-intravenous administration with
the same drug following intravenous administration
 For drugs administered intravenously, bioavailability is
100%
 Determination of the best administration route
larextravascu
ravenousint
ravenousint
larextravascu
Dose
Dose
AUC
AUC
F 
8

9. Relative Bioavailability
 Compares the bioavailability of a formulation
(A) of a certain drug when compared with
another formulation (B) of the same drug,
usually an established standard.
1larextravascu
2larextravascu
2larextravascu
1larextravascu
rel
Dose
Dose
AUC
AUC
F 
9

10. 10
Plasma concentration time
profile
Cmax
Tmax
AUC
time
concentration
Tmax

11. Therapeutic Relevance
11

12. Concept of Equivalents
 Pharmaceutical equivalents
 equal amounts of the identical active drug ingredient,
(i.e. the same salt or ester of the therapeutic moiety)
 identical dosage forms
 not necessarily containing the same inactive ingredients
 Pharmaceutical alternatives
 identical therapeutic moiety, or its precursor
 not necessarily the same:
• salt or ester of the therapeutic moiety
• amount
• dosage form
12

13. 13
Pharmaceutical Equivalents
Possible Differences
 Drug particle size
 Excipients
 Manufacturing
Equipment or
Process
 Site of
manufacture
Test Reference
Could lead to differences in product performance
in vivo
 Possible Bioinequivalence

14. Bioequivalence
Two products are bioequivalent if
 They are pharmaceutically equivalent
 Bioavailabilities (both rate and extent) after
administration in the same molar dose are similar to
such a degree that their effects can be expected to be
essentially the same
14

15.  Bioequivalence
 Pharmaceutical equivalent / alternative of the test product,
 when administered at the same molar dose,
 has the rate and extent of absorption
 not statistically significantly different from that of the
reference product.
15

16.  Therapeutic equivalence
Two products are therapeutically equivalent if
 pharmaceutically equivalent
 their effects, with respect to both efficacy and safety,
will be essentially the same as derived from appropriate
studies
◦ bioequivalence studies
◦ pharmacodynamics studies
◦ clinical studies
◦ in vitro studies
16

17. Interchangeable pharmaceutical
products
If a product is demonstrated to be
therapeutically equivalent to a reference
product, then the products are considered
interchangeable.
17

18. Measurement
of bioavailability
In vitro In vivo
18

19. Bioequivalence Studies
Basic Design
Considerations
19

20. Study Design
 Good experimental design, enhances the power of the study
 Depends on: question to be answered, nature of reference
drug/ dosage form, benefit-risk ratio
 As far as possible, the study should be of crossover design &
suitably randomized
 Ideal design: Randomized two-period, two-sequence,Crossover
design with adequate washout period
 If the half-life is long: Parallel design
 For highly variable drugs: Replicate design
20

21. Fasting study
 Bioequivalence studies are usually evaluated by a single-
dose, two-period, two-treatment, two-sequence, open-label,
randomized crossover design comparing equal doses of the
test and reference products in fasted, adult, healthy
subjects.
 This study is required for all immediate-release and
modified-release oral dosage forms.
 Both male and female subjects may be used in the study.
 Blood sampling is performed just before (zero time) the
dose and at appropriate intervals after the dose to obtain an
adequate description of the plasma drug concentration–time
profile.
21

22.  The subjects should be in the fasting state (overnight fast of at
least 10 hours) before drug administration and should
continue to fast for up to 4 hours after dosing.
 No other medication is normally given to the subject for at
least 1 week prior to the study.
 In some cases, a parallel design may be more appropriate for
certain drug products, containing a drug with a very long
elimination half-life.
 A replicate design may be used for a drug product containing
a drug that has high intrasubject variability.
22

23. Fed state
Define time of drug administration and food intake,
(e. g. drug intake within 30 min. before, immediately
before or after the standardised meal)
High fat meal may serve to investigate the worst case“
scenario
♦ Sampling
♦ Number of samples
♦ Sampling times (Cmax!)
♦ Time of sampling (extrapolated AUC max. 20 %)
♦ Wash-out-phase (not less than 5 half-lives)
23

24. Sampling times
Appr. 3 – 4 to describe drug “input”
Appr. 3 sampling times around peak concentration
Appr. 3 – 4 to describe elimination
Number of samples
sufficient to “describe” at least 80 % of total AUC
usually ~12– 18 samples (minimum)
24

25. References
 Leon Shargel, Susanna wu-pong, Andrew Yu. Applied
biopharmaceutics and pharmacokinetics. 6th edition, pg no-
417-421.
 D. M. Brahmankar, S.B. Jaiswal; “Biopharmaceutics &
Pharmacokinetics”; first edition, 12th reprint; Vallabh
Prakashan; 339 – 343.
25

26. 26