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

Fang Tang; Rui Zhou; Zeneng Cheng; Guoping Yang; Aiqiao Chen; Zhi Liu; Hongyi Tan; Shuang Yang; Sanwang Li; Lingli Mu; Peng Yu

doi:10.1016/j.apsb.2015.10.003

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

Acta Pharm Sin B. 2016 Jan;6(1):71-8. doi: 10.1016/j.apsb.2015.10.003. Epub 2015 Nov 17.

Authors

Fang Tang¹, Rui Zhou¹, Zeneng Cheng¹, Guoping Yang², Aiqiao Chen³, Zhi Liu⁴, Hongyi Tan², Shuang Yang², Sanwang Li¹, Lingli Mu⁵, Peng Yu¹

Affiliations

¹ School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
² The Third Xiangya Hospital, Central South University, Changsha 410013, China.
³ School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; Hunan Tiger-Xiangya R&D Company Ltd., Changsha 410013, China.
⁴ Hunan Tiger-Xiangya R&D Company Ltd., Changsha 410013, China.
⁵ Medical College, Hunan Normal University, Changsha 410006, China.

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.

Keywords: 3-Hydroxy-agomelatine; 7-Desmethyl-agomelatine; Agomelatine; Chinese subjects; Generic drug; High variability; Reference-scaled average bioequivalence.