Evaluation of Performance of the Truncated Area Under Curve (AUC) as a Primary Pharmacokinetic Parameter in Bioequivalence Studies

Abstract

Background and Objective: Prolonged pharmacokinetic sampling is a challenge for successful conduction of the bioequivalence studies for drugs having long elimination half-lives. The regulatory authorities have recommended an alternative to consider the partial AUC (AUC0-72) for studying bioequivalence. However, the results obtained from such truncated approach are not consistent and needs further exploration. We have investigated the suitability of truncated AUC in the fi eld of bioequivalence. Methods: The bioequivalence studies conducted with conventional approach for Bicalutamide, Topiramate and Amitriptyline having long elimination half-lives were investigated. The pharmacokinetic data obtained from these studies was truncated at 72hrs and 2 half-lives post dose. The 90% confi dence intervals constructed for the ratios of means of log-transformed partial AUC (at 72hrs and 2 half-lives post dose) were compared individually with those of the total AUC. The intra-subject variability obtained for partial AUC at 72hrs and 2 half-lives post dose was compared individually for percentage change from that of the total AUC. Results: No change in the study outcome irrespective of the point of truncation of AUC was observed. The 90% confi dence intervals constructed for the ratio of means of log-transformed partial AUC (at 72hrs and 2 half-lives post dose) were well within the acceptable bioequivalence criteria of 0.8-1.25. The intra-subject variability for AUC was not infl uenced irrespective of the point of truncation of AUC. Conclusion: Limiting the pharmacokinetic sample collection period to 72 hours in bioequivalence studies for the drugs having long elimination half-lives is equally accurate and sensitive alternative to the conventional approach.