Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis

Abstract

Introduction: Most of the antipsychotics and antidepressants are metabolized by CYP2C19 and CYP2D6 enzymes. Both CYP2D6 and CYP2C19 genes are polymorphic and metabolic capacity of the enzymes is genotype-determined. Homozygous null allele carriers do not possess active enzyme, and they are referred to as CYP2C19 or CYP2D6 poor metabolizers (PM). Certain genotypes do not abolish the enzyme completely, but they do cause drastic reduction of metabolic capacity and carriers of such genotypes are referred to as intermediate metabolizers (IM). It is known that CYP2C19 and CYP2D6 PM and IM status cause increase in exposure of certain antidepressants and antipsychotics; however, due to small sample size of the previously published studies, the magnitude of this effect still cannot be estimated with sufficient precision. Therefore, the aim of this meta-analysis was to pool all these studies and estimate the magnitude of drug exposure increase caused by CYP2C19 and CYP2D6 PM and IM status, compared with normal metabolizers (NM) to the best possible degree. Methods: The inclusion of the drugs used for the literature survey for meta-analysis was based on the list of new generation antidepressants [1] and antipsychotics [2]. These drugs were screened for inclusion by the PubMed search *DrugName AND (CYP2C19 OR CYP2D6). The studies were included in the meta-analysis if (1) the patients were genotyped for CYP2C19 or CYP2D6; (2) adequate sorting of patients into NM, IM, and PM was possible; (3) the study included at least three patients per subgroup; and (4) drug exposure was measured in representative way by: (a) dose normalized area under plasma level (time) curve, (b) dose normalized steady state plasma levels, or (c) apparent total clearance of the drug from plasma after oral administration (CL/F, reciprocal value represented the drug exposure). Meta-analysis for a specific drug was performed if three or more studies met the inclusion criteria. Drug exposure head-to-head comparisons were made between PM or IM subjects and the NM subject group, which served as a reference. Heterogeneity across the studies was assessed using Cochran's Q test at a given significance level and the percentage of total variability across the studies attributable to heterogeneity was quantified using I2 value. Magnitude of increase is presented as: Odds ratio (95% Confidence interval) Results: Based on the outcome of the literature survey, it was possible to perform meta-analysis for escitalopram, venlafaxine, risperidone, and aripiprazole. Escitalopram exposure was 1.37-fold (1.30-1.44) increased in CYP2C19 IM and 2.44-fold (2.27-2.61) increased in CYP2C19 PM. Venlafaxine exposure was not significantly changed in CYP2D6 PM, 1.10 (0.99-1.22). Risperidone and aripiprazole exposure increased was similar for CYP2D6 IM and PM. Risperidone exposure was 1.42 (1.36-1.51) increased in CYP2D6 IM and PM admixed. Aripiprazole exposure was 1.52 (1.45-1.58) increased in CYP2D6 IM and PM admixed. Conclusions: According to the results, reducing escitalopram dose by 60% in CYP2C19 PM and by 30% in CYP2C19 IM are appropriate dosing decision. Next, reducing risperidone and aripiprazole dose by 30% in CYP2D6 PM is appropriate dosing decision. Finallytract, CYP2D6 metabolizer status is not clinically relevant in venlafaxine dosing.