Physiologically Based Pharmacokinetic Modelling to Describe the Pharmacokinetics of Risperidone and 9-Hydroxyrisperidone According to Cytochrome P450 2D6 Phenotypes

Background and Objectives The genetic polymorphism of cytochrome P450 (CYP) 2D6 is characterized by an excessive impact on positive and adverse drug reactions to antipsychotics, such as risperidone. Consequently, the pharmacokinetics of the drug and metabolite can be substantially altered and exhibit a high variability between the different phenotypes. The goal of this study was to develop a physiologically based pharmacokinetic (PBPK) model considering the CYP2D6 genetic polymorphism for risperidone and 9-hydroxyrisperidone (9-OH-RIS) taking CYP3A4 into account. Additionally, risperidone dose adjustments, which would compensate for genetically caused differences in the plasma concentrations of the active moiety (sum of risperidone and 9-OH-RIS) were calculated.