study design for bioavailability and bioequivalence

 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).

 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.

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.

 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.

 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

 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)

 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.

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

 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

STUDY DESIGN FOR
THE ASSESSMENT OF
BIOAVAILABILITY AND
BIOEQUIVALENCE

 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.

 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

 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.

 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 .

 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

 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.

Subjects Period 1 Period 2
1-8 T S
9-16 S T

 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

 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.

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

 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.

Treatment A Treatment B
1 2
3 4
5 6
7 8
9 10
11 12

 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
)

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

STATISTICAL CONCEPTS IN
ESTIMATION OF
BIOAVAILABILITYAND
BIOEQUIVALENCE

 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

 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)

 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).

 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-∞).

study design for bioavailability and bioequivalence

study design for bioavailability and bioequivalence

study design for bioavailability and bioequivalence

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