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

In bioequivalence studies, the first blood or plasma sample taken after dos ing sometimes yields a higher assayed drug concentration than any samples d rawn thereafter. This circumstance ('first C-max' or 'FCM'), is usually con sidered undesirable, since a 'true C-max' requires that the sampled concent rations immediately preceding and immediately after the 'true C-max' concen tration should be lower than the 'true C-max' concentration. Therefore, a q uestion arises whether the presence of FCM in a bioequivalence study affect s the power and accuracy of the computed statistical confidence interval (C I) for C-max. This study examines what effect, if any, the inclusion or exc lusion 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 st udies. Actual experimental study data as well as data from simulated studie s were evaluated. In the simulated studies, up to half of the study subject s exhibited FCM, and various levels of intrasubject variability were incorp orated into the absorption rate constant. The two one-sided tests procedure was used to assess equivalence of C-max for the test versus reference prod ucts when either a complete set of C-max data was analysed (designated 'CCm ax'), which included subjects with FCM profiles; or a truncated set of data was analysed (designated 'TCmax'), that excluded all subjects with FCM. Th e results showed that the CCmax metric had greater statistical power and co mparable or greater statistical accuracy compared to TCmax for both bioequi valent 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 ra te of absorption (i.e. C-max) was not significantly affected. Consequently, this study shows that, in the analysis of data from conventional in vivo b ioequivalence studies, the inclusion of 50% of the subjects exhibiting FCM does not greatly impact the statistical results obtained for C-max. Publish ed in 2000 by John Wiley & Sons, Ltd.