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
Highlights
Agomelatine brings a new concept to the antidepressant treatment
For new generic agomelatine products/formulation with clinical trial permission of China Food and Drug Administration (CFDA), bioequivalence (BE) evaluation is one of the pivotal clinical studies required in support of its marketing application
We aim to investigate the intra-subject coefficient of variability (CV) of agomelatine in Chinese healthy volunteers, and propose an adjusted BE assessment strategy for agomelatine
Summary
Agomelatine brings a new concept to the antidepressant treatment. Compared to the other antidepressant drugs (e.g. mianserin and mirtazapine), agomelatine owns its melatonin (MT1 and MT2) agonist properties and a serotonin 5-HT2C antagonist effect simultaneously [1,2]. For new generic agomelatine products/formulation with clinical trial permission of China Food and Drug Administration (CFDA), bioequivalence (BE) evaluation is one of the pivotal clinical studies required in support of its marketing application. Due to the highly variable feature, a standard number of subjects (e.g., 18–24) may not be able to demonstrate the bioequivalence of the generic products and their corresponding reference products using a twoway crossover design. In order to obtain adequate statistical power to meet BE limits, the subjects number for BE study of highly variable drugs need to be calculated based on the intra-subject coefficient of variability (CV) of pharmacokinetic (PK) parameters (Cmax and AUC) of reference products [6,7,8]. The intra-subject CV data of agomelatine in Chinese healthy volunteers has not been reported. We aim to investigate the intra-subject CV of agomelatine in Chinese healthy volunteers, and propose an adjusted BE assessment strategy for agomelatine
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