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We are conducting a single vs. multiple dose comparative
bioavilability study (400 mg of test product and 200 mg of reference
The test product will be dosed once and the reference product will be
1. For this study how do we go about doing the pharmacokinetic and
2. What are all the pharmacokinetic parameters we should include?
3. One of over objective is "To compare the oral dose bioavailability
of test and reference product. To find the bioavailability of the
drug what formula should I have to use?
I will be grateful to listen to your suggestions
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The following message was posted to: PharmPK
A few points for you to consider:
A) Make sure that you can document liner PK in the dose range 200-400
B) Assess relative bioavailability both after single and repeated dose.
C) Assess time to steady state to compare bioavailabilities of the
two formulations when the PK of your drug are at steady state.
C) Assess time-dependency by applying the superimposition principle
(for each formulation compare the AUCinf after a single dose with AUC
within a dosing interval at steady state with dosing interval set at
24 h for test and 12 h for reference (within each formulation the
AUCs should not differ significantly).
D) At steady state compare AUC within a dosing interval after dose
normalization (AUC12/200 for reference and AUC24/400 for test).
E) after a single dose relative bioavailability should be assessed
using dose-normalised AUCinf.
Study should be randomised and crossed over with ANOVA to compare
both time-dependency and relative bioavailability (use FDA
bioequivalence guideline for acceptance criteria and details of the
factors to be included in the ANOVA).
Test Cmax and AUC as described above whereas use non parametric test
for Tmax (again FDA guideline for details).
I would not compare any other parameters unless you really need it.
Depending on the therapeutic area sometimes you might want to test
Thalf, CL etc. etc.
Finally, unless you have previous PK data that allow you assess intra-
subject variability, I would suggest performing a pilot study to make
sure that you select the correct sample size in the pivotal study.
Stefano Persiani, PhD
Drug Metabolism, Pharmacokinetics and Dynamics
Rotta Research Laboratorium
The R&D Division of Rottapharm SpA
Via Valosa di Sopra, 9
20052 Monza (MI)
T +39 039 7390396
F +39 039 7390371
C +335 7840850
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