Evaluation of the bioequivalence of highly-variable drugs and drug products.
OBJECTIVE
To establish procedures for the effective evaluation of bioequivalence (BE) for highly-variable drugs and drug products (HVD/P).


METHODS
2- and 4-period crossover BE studies with 24 subjects were simulated which generally assumed within-subject coefficients of variation of 40%. The relationship between the fraction of studies in which BE was accepted (the statistical power) and the ratio of geometric means (GMR) of the two formulations was evaluated for various methods of analysis. These included, primarily, scaled average BE (ABE), the corresponding approach of expanding BE limits (BEL), and, for comparison, unscaled ABE and scaled individual BE (IBE).


RESULTS
Scaled ABE and expanding BEL showed very similar properties in both 2- and 4-period studies. They had steeper power curves than scaled IBE. Unscaled ABE had very low statistical power. The acceptance of BE by unscaled and scaled ABE and expanding BEL was almost independent of subject-by-formulation interaction and the ratio of within-subject variations of the two formulations. By contrast, the conclusions reached by scaled IBE were strongly affected by these parameters.


CONCLUSIONS
Scaled ABE and expanding BEL evaluate BE effectively for HVD/P in both 2- and 4-period investigations. However, additional, useful information can be obtained from 4-period studies.
Tothfalusi
L
L
Semmelweis University of Budapest, Department of Pharmacodynamics, Hungary.
Endrenyi
L
L
Midha
K K
KK
Rawson
M J
MJ
Hubbard
J W
JW
D000704:Analysis of Variance; D003198:Computer Simulation; D016001:Confidence Intervals; D018592:Cross-Over Studies; D006801:Humans; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000378:metabolism* / Q000592:standards; D010599:Pharmacokinetics; D012015:Reference Standards; D012016:Reference Values; D013810:Therapeutic Equivalency
D004364:Pharmaceutical Preparations