title: Evaluation of the highly variable agomelatine pharmacokinetics in Chinese healthy subjects to support bioequivalence study.
abstract: OBJECTIVE
  We aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy.
  
  
  METHODS
  A 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.
  
  
  RESULTS
  The 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%).
  
  
  CONCLUSIONS
  Agomelatine 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.
  
  
  BACKGROUND
  ChiCTR.org ChiCTR-TTRCC-13003835.
authors.affiliation: Department of pharmacy, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Pei
authors.affiliation: Department of pharmacy, Changde First People's Hospital, Changde, Hunan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Zhe-Yi
authors.initials: ZY
authors.lastname: Hu
authors.affiliation: Department of pharmacy, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Shi-Kun
authors.initials: SK
authors.lastname: Liu
authors.affiliation: Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Tan
authors.affiliation: Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Cheng-Xian
authors.initials: CX
authors.lastname: Guo
authors.affiliation: Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Ran-Ran
authors.initials: RR
authors.lastname: Zhang
authors.affiliation: Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yu-Xia
authors.initials: YX
authors.lastname: Xiang
authors.affiliation: Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Yang
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D044466:Asian People; D004305:Dose-Response Relationship, Drug; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D012015:Reference Standards; D013810:Therapeutic Equivalency; D013997:Time Factors; D055815:Young Adult; D009281:Naphthalenes
chemical_list: D000081:Acetamides; C084711:agomelatine; D009281:Naphthalenes