To evaluate the influence of sex and CYP2D6 genotype on mirtazapine disposition within two bioequivalence studies in healthy volunteers.Methods:
Seventy-two healthy volunteers were included in two standard 2 × 2 crossover bioequivalence trials. Subjects received a single 30-mg oral dose of each mirtazapine formulation in each study period. Plasma concentrations were measured from 0 to 96 or 120 h by a HPLC with coupled mass spectrometry validated method. CYP2D6 genotyping was available for 68 subjects that were classified into three phenotypic groups depending on the number of active gene copies: extensive/ultrarapid metabolizers (UM-EM), intermediate (IM) and poor metabolizers (PM). To evaluate the influence of sex and genotype on mirtazapine disposition we performed a linear mixed model for repeated measures. Pharmacokinetic data were log-transformed and AUC and Cmax adjusted to the administered dose/weight. Factors included in the model were centre, formulation, period, sequence, sex and genotype as fixed effects, and subject nested sequence × sex × genotype as random one. A second model was also performed adding the interaction sex × genotype to the previous model.Results:
Mirtazapine disposition evaluated as AUC0–∞ is influenced by sex (p = 0.007) and CYP2D6 phenotype group (p = 0.01). Attending to the theoretical figures provided by the model, mean (95% CI) dose/weight adjusted AUC0–∞ (ng h/ml)/(mg/kg) is 1516.62 (1411.27–1628.22) in EM/UM, 1613.63 (1482.14–1758.55) in IM and 2049.28 (1779.78–2357.24) in PM. In the case of Cmax these figures also show a trend to higher values in PM, but it did not reach statistical significance. Females show a lower dose/weight adjusted AUC0–∞: 1594.39 (1477.70–1720.28) vs. 1837.65 (1694.67–1992.70). On the contrary dose/weight adjusted Cmax is higher in females than in males: 38.33 (34.79–42.28) vs. 32.66 (29.44–36.21).Conclusions:
Both CYP2D6 genotype group and sex influence the disposition of mirtazapine in healthy volunteers and confirm reported data in the literature obtained by different methods. No sex-by-genotype interaction could be detected.