The duration of measuring partial AUCs for the assessment of bioequivalence.
OBJECTIVE
To determine favourable sampling conditions for assessing bioequivalence by the comparison of partial AUCs in the early phase of concentration-time profiles.


METHODS
Two-period crossover trials were simulated. They assumed a wide range of the ratios of absorption rate constants of the test (T) and reference (R) formulations (kaT/kaR). Averages and standard deviations of the corresponding ratios of simulated partial AUCs (AUCpT/AUCpR) were determined together with the statistical power of assessing bioequivalence, i.e., the percentage of simulated trials in which bioequivalence was declared.


RESULTS
The power for stating bioequivalence was high when AUCp was recorded until the earlier rather than the later of two peaks in each subject. Similarly, power was comparatively high when AUCp was measured until the time of the reference peak instead of multiples of this time. Power was high also when AUCp was determined until the fixed true, population mean time of the reference formulation instead of multiples of this time. The pattern for the kinetic sensitivity parallelled that found for the power, while the standard deviations changed generally in the opposite direction.


CONCLUSIONS
The effectiveness (power) of evaluating bioequivalence in the early phase of concentration-time profiles by partial AUCs generally decreases when the duration for measuring the metric is extended. Among the investigated designs, determination of partial AUCs until the earlier of two peaks in each subject is the most powerful.
Endrenyi
L
L
University of Toronto, Department of Pharmacology, Ontario, Canada.
Csizmadia
F
F
Tothfalusi
L
L
Balch
A H
AH
Chen
M L
ML
D019540:Area Under Curve; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008962:Models, Theoretical; D010599:Pharmacokinetics; D013810:Therapeutic Equivalency