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Chem Pharm Bull (Tokyo). 2017 Jun 1;65(6):524-529. doi: 10.1248/cpb.c16-00866. Epub 2017 Apr 8.

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.

Author information

1
Phase I Clinical Unit, China-Frontage USA, The First Hospital of Jilin University.
2
Department of Neurology, The First Hospital of Jilin University.
3
Department of Geriatrics, The First Hospital of Jilin University.
4
The Second Hospital of Jilin.
5
Department of Clinical Laboratory, The Second Hospital of Jilin.
6
Department of Hepatology, The First Hospital of Jilin University.

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-t and t1/2 were 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 Cmax and AUC0-t were 78.3 and 61.8%, respectively. The inter-individual coefficients of variance (CVs) of Cmax and AUC0-t were 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.

KEYWORDS:

agomelatine; bioequivalence; inter-individual variation; intra-individual; pharmacokinetic

PMID:
28392509
DOI:
10.1248/cpb.c16-00866
[Indexed for MEDLINE]
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