Evaluation of the Highly Variable Agomelatine Pharmacokinetics in Chinese Healthy Subjects to Support Bioequivalence Study

Abstract

ObjectivesWe aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy.MethodsA single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples.ResultsThe intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for Cmax and AUC0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%).ConclusionsAgomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies.Trial RegistrationChiCTR.org ChiCTR-TTRCC-13003835

Bioequivalence and Pharmacokinetic Profiles of Agomelatine 25-mg Tablets in Healthy Chinese Subjects: A Four-Way Replicate Crossover Study Demonstrating High Intra- and Inter-Individual Variations

“…3,21,22) In Caucasians, the interindividual variability of the AUC after the oral administration of agomelatine varied in different reports (100-150% CV).…”

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

“…There are a few reports in the literature on the pharmacokinetics of agomelatine in Chinese population. Pei et al 14 investigated the CV(%) of agomelatine in 16 Chinese healthy male volunteers and showed significant ethnic differences between Chinese and Caucasian subjects in C max and AUC 0– t whereas no ethnic differences in T max or t 1/2 were found. Less obvious first-pass effects in Chinese subjects may partially account for why both C max and AUC of Chinese males were much higher than those of Caucasian males.…”

“…Although agomelatine pilot data are published for Caucasians, they may not be applicable to the bioequivalence in other populations due to ethnic differences. Pei et al 14 investigated the intra-subject CV of agomelatine in healthy Chinese volunteers. Results showed notable intra-subject variability in AUC 0– t (CV=43.52%) and C max (CV=78.34%).…”

Agomelatine pretreatment prevents development of hyperglycemia and hypoinsulinemia in streptozotocin‐induced diabetes in mice

“…It is extensively protein bound (95%) and its elimination half-life is 2.3 h [27]. Therefore, an adjusted bioequivalence assessment strategy has been proposed [28]. As we preferred in the present experiment, parenteral use of agomelatine seems to be more effective and is necessary to see its diabetic effects exactly.…”