Influence of sex and CYP2D6 genotype on mirtazapine disposition, evaluated in Spanish healthy volunteers

AimsTo evaluate the influence of sex and CYP2D6 genotype on mirtazapine disposition within two bioequivalence studies in healthy volunteers.MethodsSeventy-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.ResultsMirtazapine 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).ConclusionsBoth 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.