Bioequivalence Study of Amitriptyline Hydrochloride Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions

Abstract

Purpose: This study compares the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of amitriptyline hydrochloride tablets, and assesses the bioequivalence of the two products in healthy Chinese volunteers to obtain sufficient evidence for the marketing approval of the generic drug.

Materials and methods: A randomized, open-label, two-period crossover study (clinicaltrials.gov, NCT03646526) was conducted under both fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a single 25 mg dose of either the test or the reference formulation, followed by a 3-week washout period. Blood samples were collected until 144 h following administration. The pharmacokinetic parameters were acquired based on the concentration-time profiles, including the areas under the plasma concentration-time curve (AUC0-t, AUC0-∞), the peak plasma concentration (Cmax), the time to achieve Cmax (Tmax), and the elimination half-life (t1/2). The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) of amitriptyline were acquired for bioequivalence analysis, and values of these parameters for nortriptyline were used for comparison of therapeutic outcomes. Safety assessments included laboratory tests, physical examination, vital signs, and incidence of adverse events (AEs).

Results: The values of t1/2 and Tmax for amitriptyline were not significantly different between the test and reference products under both fasting and fed conditions (P > 0.05). The GMRs of Cmax, AUC0-t, and AUC0-∞ between the two products, and corresponding 90% CIs, were all within the range of 80% to 125% under both fasting and fed conditions. The test and reference products were well tolerated and did not elicit serious adverse events.

Conclusion: This study demonstrated that the generic and reference products were well tolerated by the subjects and bioequivalent, according to the rate and extent of the drug absorption.

Keywords: amitriptyline hydrochloride; bioequivalence; nortriptyline; pharmacokinetics.

Conflict of interest statement

Hunan Dongting Pharmaceutical Co., Ltd. (Hunan, China) funded our study, which was the manufacturer of amitriptyline hydrochloride tablets. The funder had not any influence on data collection and analysis, manuscript preparation, and decision to publish. All authors report no conflicts of interest in this work.

© 2020 Zhai et al.

Figures

Figure 1

Study design and disposition of subjects.

Figure 2

Mean plasma concentration-time profiles of amitriptyline (A) and nortriptyline (B) after single oral administration of reference and test amitriptyline hydrochloride tablet in 24 healthy Chinese volunteers under fasting condition. Data represent the mean value for the 24 volunteers, and error bars represent the SD.

Figure 3

Mean plasma concentration-time profiles of amitriptyline (A) and nortriptyline (B) after single oral administration of reference and test amitriptyline hydrochloride tablet in 24 healthy Chinese volunteers under fed condition. Data represent the mean value for the 24 volunteers, and error bars represent the SD.