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study design for bioavailability and bioequivalence
1.
2. Bioavailability is the fraction of an administered dose of
unchanged drug that reaches the systemic circulation.
when a medication is administered intravenously, its
bioavailability is 100%.
when a medication is administered via other routes (such as
orally), its bioavailability generally decreases (due to
incomplete absorption and first-pass metabolism).
3. There are two types….
1. Absolute bioavailability - It is the fraction of
the drug absorbed through non-intravenous
administration compared with the corresponding
intravenous administration of the same drug.
4. 1. Relative Bioavailability - Relative
bioavailability measures the bioavailability
(estimated as the AUC) of a formulation (A) of a
certain drug when compared with another
formulation (B) of the same drug.
5. Bioequivalence is a term
in pharmacokinetics used to assess the
expected in vivo biological equivalence of two
proprietary preparations of a drug.
In order to determine that two medicines are
bioequivalent there must be no more than a 20%
difference between the AUC and Cmax.
6.
7. In vivo bioequivalence studies are conducted
in the usual manner as discussed for
bioavailability studies, i.e. ……
1. Pharmacokinetic Methods
A. Plasma level-time study
B. Urinary Excretion studies
2. Pharmacodynamic Methods
A. Acute pharmacological response
B. Therapeutic response
8. The parameter that are useful in determining the
bioavailability of a drug from a drug product based
on indirect methods…
Plasma data
1. Time of peak plasma conc.( t max)
2. Peak plasma conc.(Cmax)
3. Area under the curve (AUC)
Urine data
1. Rate of drug excretion in the urine (dXu /dt)
2. Cumulative amount of drug excreted in urine (Xu)
3. Time for maximum urinary excretion (tu)
9. In order to estimate the bioavailability of a drug
product accurately by this method, the following
criteria should be met….
1. An established dose- related response curve
2. An easily measurable pharmacological response
such as heart rate, ECG, blood pressure, pupil
diameter etc.
10. A. Study objective
B. Study design
Experimental design
Wash out period
Drug products (test and std)
Route of drug administration
Dosage regimen
Frequency and duration of sampling
Randomization of drug administration
Single versus multiple dose study design
11. Subjects
i. Healthy versus patients
ii. Subject selection
Medical history
Physical examination
Laboratory test
iii. Study conditions
Analysis of biological fluids
C. Methods of assessment of bioavailability
D. Analysis and presentation of data
13. A good experimental design enhances the power
of study.
It depends upon the question to be answered,
nature of reference drug/dosage form and risk
benefit ratio.
The study should be of cross over design and
suitably randomized.
14. Healthy adult volunteers
Age: 18-45 years
Age/ sex representation corresponding to
therapeutic and safety profile.
Women: pregnancy test prior to 1st and last dose
of study
Teratogenic Drugs: male volunteers
15. The selected subjects should be maintained on a
uniform diet and none of them should taken any
drug at least one week prior to the study.
Fasting period before the administration.
Standard diet to given after fasting, fluid intake
and volume to be allowed.
16. The time interval between two treatments is
called “wash-out period”.
It is require for the elimination of the
administered dose of a drug so as to avoid
carryover effect.
Washout period is a function of the half-life and
the dose of the drug administered, the number of
washout period in a study depends on type of
cross-over design used and the number of
formulations to be evaluated .
17. There are various study designs….
1. Two Period cross-over design
2. Latin Square Design
3. Balance incomplete Block Design
4. Parallel Group Design
5. Replicate Cross-over study design
18. For two formulations
Even no. of subjects
Randomly divided into 2 equal groups.
First period, each member of one group receive a
single dose of the test formulation, each member
of the other group receive the standard
formulation.
20. For more than two Formulations.
A group of volunteers will receive formulation in
sequence..
Volunteer No. Period 1 Period 2 Period 3
1 A B C
2 B C A
3 C A B
21. More than 3 formulations, Latin square design
will not be ethically advisable
Because each volunteer mat require drawing of
too many blood samples.
If each volunteer expected to receive at least two
formulation, then such a study can be carried out
using BIBD.
22. Volunteer No. Period 1 Period 2
1 A B
2 A C
3 A D
4 B C
5 B D
6 C D
7 B A
8 C A
9 D A
10 C B
11 D B
12 D C
23. Even no. of subjects in two groups.
Each subject receive a different formulation.
No washout necessary
For drugs with long half life.
This is also called as non- crossover study.
25. For highly variable drugs
Allows comparisons of within- subject variance
Reduce the number of subjects needed
Four period, two sequence, two formulation
design( recommended)
Three period, two sequence ( partially replicated
)
26. Period 1 2 3 4
Group A T R T R
Group B R T R T
Period 1 2 3
Group A T R T
Group B R T R
28. In our study statistical analysis will be performed
on PK data of subjects by using SAS statistical
software .
If they cannot be estimated, the subject will be
excluded from the pertaining pharmacokinetic
analysis. If necessary an unequal no. of subjects
per sequence will be used
29. The various pharmacokinetic parameters (AUC (AUC 0-
t and AUC 0-∞), Cmax) derived from the plasma
concentration-time curve are subjected to ANOVA in
which the variance is partitioned into components due to
subjects, periods and treatments.
The classical null hypothesis test is the hypothesis of
equal means: μT=μR (i.e. products are bioequivalent),
where - μT and μR represent the expected mean
bioavailabilities of the test and reference formulations,
respectively.
The alternate hypothesis therefore is H: μT ≠ μR (i.e.
products are bioinequivalent)
30. An F test will be performed to determine the
statistical significance of the effects involved in
the model at a significance level of 5%
(alpha=0.05).
31. Ratio of least squares means for test and
reference listed drugs (RLD) formulations will be
computed and reported for Log-transformed
pharmacokinetic parameters C max, AUC (0-t)
and AUC (0-∞).