title: 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.
abstract: The present study was designed to assess the bioequivalence of two agomelatine formulations (25-mg tablets) in healthy Chinese male subjects. This single-dose, open-label, randomized, four-way replicate study with a 1-week washout period was conducted in 60 healthy Chinese male volunteers under fasting conditions. Blood samples were collected over a 12-h period after a single dose of the 25-mg agomelatine test (T) formulation or a reference (R) formulation, and the drug concentrations were assayed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated using a non-compartmental model. Bioequivalence between the formulations was assessed. Tolerability and safety were monitored by physical examination, electrocardiogram (12-lead ECG), clinical laboratory tests, and adverse events (AEs). A total of 56 out of 60 subjects completed the study. No AEs were observed. The values of maximum plasma concentration (Cmax), maximum concentration (Tmax), area under curve (AUC)0-tand t1/2were 12.032 ng/mL, 0.658 h, 12.637 ng·h/mL, and 0.813 h, respectively, for the test formulation, and 10.891 ng/mL, 0.709 h, 11.572 ng·h/mL, and 0.96 h, respectively, for the reference formulation. The intra-individual variability of Cmaxand AUC0-twere 78.3 and 61.8%, respectively. The inter-individual coefficients of variance (CVs) of Cmaxand AUC0-twere approximately 100%. The 90% confidence intervals for the ratio of means for the log-transformed Cmax(97.7-124.9%), AUC0-t(98.2-118%), and AUC0-∞(97.8-117.2%) were within the guideline range of bioequivalence (80-125%). The test and reference formulations of agomelatine met the regulatory criteria for bioequivalence of the Chinese Food and Drug Administration. Significant intra-individual and inter-individual variations were found.
authors.affiliation: Phase I Clinical Unit, China-Frontage USA, The First Hospital of Jilin University.
authors.forename: Cuiyun
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Neurology, The First Hospital of Jilin University.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Geriatrics, The First Hospital of Jilin University.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Phase I Clinical Unit, China-Frontage USA, The First Hospital of Jilin University.
authors.forename: Guiling
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Geriatrics, The First Hospital of Jilin University.
authors.forename: Jianmeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Second Hospital of Jilin.
authors.forename: Liying
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Clinical Laboratory, The Second Hospital of Jilin.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Hepatology, The First Hospital of Jilin University.
authors.forename: Junqi
authors.initials: J
authors.lastname: Niu
authors.affiliation: Phase I Clinical Unit, China-Frontage USA, The First Hospital of Jilin University.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Phase I Clinical Unit, China-Frontage USA, The First Hospital of Jilin University.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Phase I Clinical Unit, China-Frontage USA, The First Hospital of Jilin University.
authors.forename: Xiaojiiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Phase I Clinical Unit, China-Frontage USA, The First Hospital of Jilin University.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Phase I Clinical Unit, China-Frontage USA, The First Hospital of Jilin University.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Phase I Clinical Unit, China-Frontage USA, The First Hospital of Jilin University.
authors.forename: Chengjiao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Phase I Clinical Unit, China-Frontage USA, The First Hospital of Jilin University.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002681:China; D018592:Cross-Over Studies; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets; D013810:Therapeutic Equivalency; D055815:Young Adult; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D006993:Hypnotics and Sedatives; D013607:Tablets; C084711:agomelatine; D009281:Naphthalenes
keywords: agomelatine; bioequivalence; inter-individual variation; intra-individual; pharmacokinetic