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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
BIOAVAILABILITY AND
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-∞).