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

摘要

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 ( C _max), maximum concentration ( T _max), area under curve ( AUC )_{0– t} and t _1/2 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 C _max and AUC _{0? t} were 78.3 and 61.8%, respectively. The inter-individual coefficients of variance (CVs) of C _max and AUC _{0? t} were approximately 100%. The 90% confidence intervals for the ratio of means for the log-transformed C _max (97.7–124.9%), AUC _{0? t} (98.2–118%), and AUC _0?∞ (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.