Bioequivalence Study Of A Fixed-Dose Combination Tablet Containing Melitracen 10 mg And Flupentixol 0.5 mg In Healthy Chinese Volunteers Under Fasted And Fed Conditions

Abstract

Purpose

A fixed-dose combination (FDC) tablet of melitracen/flupentixol has been widely used for depression. The purpose of this study was to assess the safety profile and the relative bioavailability of two FDC products containing 10 mg melitracen and 0.5 mg flupentixol from two different manufacturers, in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation.

Methods

The study was designed as a single-dose, randomized, open-label, 2-period crossover study under fasted or fed conditions in healthy Chinese subjects. Twenty-four subjects (16 men and 8 women) were selected for fasted study, and another 24 cases (16 men and 8 women) were in fed study. Each subject was randomized at the beginning to receive either a single dose of the reference FDC or the test FDC tablet during the first period. Following two-week washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 144 hrs after administration. Pharmacokinetic parameters, including C_max, T_max, AUC_0-t, AUC_0-∞, t½, CL/F, and V_d/F were acquired based on the time versus concentration profiles. Then, the geometric mean ratios (GMR) and corresponding 90% CIs were calculated for the determination of bioequivalence analysis. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events (AEs).

Results

The present study has clearly indicated the test and the reference FDC products are bioequivalent in terms of rate and extent of drug absorption. GMR of C_max, AUC_0–t, and AUC_0-∞ for both flupentixol and melitracen between the two formulation FDC products, and corresponding 90% CIs, were all within the range of 80% to 125% under fasted or fed conditions. Both the test and the reference FDC products indicated good tolerance in all volunteers. Chinese Clinical Trials Registry identifier: CTR20171256.

Keywords:

• bioequivalence
• melitracen
• flupentixol
• pharmacokinetics
• fixed-dose combination tablet

Acknowledgments

This work was supported by Haisco Pharmaceutical Group. The authors would like to thank Wei Xu, Weiping Chen, Zhuojun Zhou and Liya Zheng from First Affiliated Hospital, College of Medicine, Zhejiang University, for their clinical assistance. Other coworkers, namely Jian Liu, Xingjiang Hu, Yunliang Zheng, Meihua Lin, Minglan Wu, Qiao Zhang, Juan Xu, Yuanfang Wang also paid a contribution during the whole study. Wuxi AppTec. took responsibility for bioanalytical parts of the study as well as the pharmacokinetics analysis, the statistical analysis, and data interpretation.

Data Sharing Statement

Individual deidentified participant data are not going to be shared. And all available data have been shown in the article. No other study-related document will be made available.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work. Lihua Wu and Chang Xu are co-first authors.

Disclosure

The authors report no conflicts of interest in this work.