CYP2D6 Genetic Polymorphisms and Risperidone Pharmacokinetics: A Systematic Review and Meta-analysis

Background : Risperidone is a second-generation antipsychotic drug metabolized to an active metabolite, 9-hydroxyrisperidone, primarily by cytochrome P450 (CYP) 2D6 and to a lesser extent by CYP3A4. The extent to which drug metabolism genetics impacts risperidone and 9-hydroxyrisperidone exposure has not been clarified. Objective : A systematic review and meta-analysis evaluated the impact of genetically defined CYP2D6 function on risperidone pharmacokinetics applying a standardized genotype–phenotype translation system. Methods : A comprehensive electronic database search identified studies reporting relationships between genetically determined CYP2D6 metabolism and risperidone pharmacokinetic properties. The exposure of risperidone or active moiety (risperidone + 9-hydroxyrisperidone) was measured by dose-adjusted steady-state serum or plasma concentration or area under the concentration-time curve as primary outcomes. Subjects were assigned to CYP2D6 poor metabolizer, intermediate metabolizer, normal metabolizer, or ultrarapid metabolizer groups using a standardized genotype–phenotype translation method. Effect sizes between groups were pooled and stratified by single or multiple dosing regimens. Results : A total of 15 studies involving 2125 adult subjects were included in the meta-analysis. Following multiple-dose oral administration, compared with CYP2D6 normal metabolizers, the risperidone dose-adjusted steady-state serum/plasma concentration was 2.35-fold higher in intermediate metabolizers (95% confidence interval [CI] 1.77–3.13, p<0.0001) and 6.20-fold higher in poor metabolizers (95% CI 5.05–7.62, p<0.0001); the active moiety dose-adjusted steady-state concentration was 1.18-fold higher in intermediate metabolizers (95% CI 1.11–1.25, p<0.0001) and 1.44-fold higher in poor metabolizers (95% CI 1.23–1.69, p<0.0001). Higher area under the concentration-time curve of risperidone and active moiety was also found in single-dose studies. Conclusion : Genetically defined impaired CYP2D6 activity is associated with increased exposure of both risperidone and risperidone + 9-hydroxyrisperidone in adults receiving oral formulations. Additional studies are needed to quantify the clinical impact of these relationships.