Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of agomelatine in Chinese subjects

摘要

The aim of this study was to apply the reference-scaled average bioequivalence（RSABE）approach to evaluate the bioequivalence of 2 formulations of agomelatine,and to investigate the pharmacokinetic properties of agomelatine in Chinese healthy male subjects.This was performed in a single-dose,randomized-sequence,open-label,four-way crossover study with a one-day washout period between doses.Healthy Chinese males were randomly assigned to receive 25 mg of either the test or reference formulation.The formulations were considered bioequivalent if 90% confidence intervals（CIs）for the log-transformed ratios and ratio of geometric means（GMR）of AUC and Cmax of agomelatine were within the predetermined bioequivalence range based on RSABE method.Results showed that both of the90% CIs for the log-transformed ratios of AUC and Cmax of 7-desmethyl-agomelatine and 3-hydroxyagomelatine were within the predetermined bioequivalence range.The 90% CIs for natural logtransformed ratios of Cmax ,AUC0–tand AUC0–∞ of agomelatine（104.42–139.86,101.33–123.83 and97.90–117.94）were within the RSABE acceptance limits,and 3-hydroxy-agomelatine（105.55–123.03,101.95–109.10 and 101.72–108.70）and 7-desmethyl-agomelatine（104.50–125.23,102.36–111.50 and101.62–110.64）were within the FDA bioequivalence definition intervals(0.80–1.25 for AUC and0.75–1.33 for Cmax).The RSABE approach was successful in evaluating the bioequivalence of these two formulations.