title: Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of agomelatine in Chinese subjects.
abstract: 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 C max of agomelatine were within the predetermined bioequivalence range based on RSABE method. Results showed that both of the 90% CIs for the log-transformed ratios of AUC and C max of 7-desmethyl-agomelatine and 3-hydroxy-agomelatine were within the predetermined bioequivalence range. The 90% CIs for natural log-transformed ratios of C max, AUC0-t and AUC0-∞ of agomelatine (104.42-139.86, 101.33-123.83 and 97.90-117.94) 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 and 101.62-110.64) were within the FDA bioequivalence definition intervals (0.80-1.25 for AUC and 0.75-1.33 for C max). The RSABE approach was successful in evaluating the bioequivalence of these two formulations.
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Tang
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: The Third Xiangya Hospital, Central South University, Changsha 410013, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; Hunan Tiger-Xiangya R&D Company Ltd., Changsha 410013, China.
authors.forename: Aiqiao
authors.initials: A
authors.lastname: Chen
authors.affiliation: Hunan Tiger-Xiangya R&D Company Ltd., Changsha 410013, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The Third Xiangya Hospital, Central South University, Changsha 410013, China.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Tan
authors.affiliation: The Third Xiangya Hospital, Central South University, Changsha 410013, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
authors.forename: Sanwang
authors.initials: S
authors.lastname: Li
authors.affiliation: Medical College, Hunan Normal University, Changsha 410006, China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Mu
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
keywords: 3-Hydroxy-agomelatine; 7-Desmethyl-agomelatine; Agomelatine; Chinese subjects; Generic drug; High variability; Reference-scaled average bioequivalence