First measured plasma concentration value as C(max); impact on the C(max) confidence interval in bioequivalence studies

Abstract

In bioequivalence studies, the first blood or plasma sample taken after dosing sometimes yields a higher assayed drug concentration than any samples drawn thereafter. This circumstance ('first C(max)' or 'FCM'), is usually considered undesirable, since a 'true C(max)' requires that the sampled concentrations immediately preceding and immediately after the 'true C(max)' concentration should be lower than the 'true C(max)' concentration. Therefore, a question arises whether the presence of FCM in a bioequivalence study affects the power and accuracy of the computed statistical confidence interval (CI) for C(max). This study examines what effect, if any, the inclusion or exclusion of FCM data has on the statistical power and accuracy of the 90% CI computed for C(max) in the analysis of results for in vivo bioequivalence studies. Actual experimental study data as well as data from simulated studies were evaluated. In the simulated studies, up to half of the study subjects exhibited FCM, and various levels of intrasubject variability were incorporated into the absorption rate constant. The two one-sided tests procedure was used to assess equivalence of C(max) for the test versus reference products when either a complete set of C(max) data was analysed (designated 'CC(max)'), which included subjects with FCM profiles; or a truncated set of data was analysed (designated 'TC(max)'), that excluded all subjects with FCM. The results showed that the CC(max) metric had greater statistical power and comparable or greater statistical accuracy compared to TC(max) for both bioequivalent and non-bioequivalent drug product formulations. Even when up to 50% of the study subjects had FCM, the power and accuracy of the 90% CI for rate of absorption (i.e. C(max)) was not significantly affected. Consequently, this study shows that, in the analysis of data from conventional in vivo bioequivalence studies, the inclusion of 50% of the subjects exhibiting FCM does not greatly impact the statistical results obtained for C(max). Published in 2000 by John Wiley & Sons, Ltd.