Population Pharmacokinetic Analysis of Centrally Acting Drugs Metabolized by CYP2D6

Abstract

A simple, sensitive, and reliable UPLC method has been developed and validated for simultaneous determination of risperidone, 9-hydroxyrisperidone and olanzapine in human plasma in vitro. newlineThe developed method has been successfully adopted to evaluate the pharmacokinetic parameters of second generation antipsychotic drugs, risperidone and its major metabolite, 9-hydroxyrisperidone, in human plasma. The metabolic ratio was higher in intermediate metabolizers (2.04 ± 0.20) as compared to normal metabolizers (1.40 ± 0.22). Our data supports these above conclusions in our sample population, i.e., poor metabolizers require half the risperidone dose than that for normal metabolizers to reduce the incidence of adverse effects. newlineCONCLUSION: newlineIn the current study, we have demonstrated significant association between the genotype status and pharmacokinetic parameter of normal subjects from our locale in South India with respect to the CYP2D6*10 genotype. Our data suggest that CYP2D6*10 polymorphism have significant association between risperidone and 9-hydroxyrisperidone pharmacokinetics. Active moiety is highly predictive of the clinical response to risperidone in healthy volunteers, which is dependent on the CYP2D6*10 genotype status. Additionally, we demonstrated that using NONMEM and multi-compartment mixed effect modelling of the population pharmacokinetics of risperidone and its metabolite, genotype has a major influence on determining the plasma concentrations of both risperidone and 9-hydroxyrisperidone. newlineThe pharmacogenetic variations in clearance of the risperidone and 9-hydroxyrisperidone may be due to differential expressions of CYP2D6 in intestinal epithelium in different genotypes of CYP2D6*10 allele. Further, this could be applied to clinical decision making such as determination of dosing intervals. We recommend that the dose of risperidone in slow metabolizers must be less that used in normal metabolizers, though it has to be confirmed in further studies in our population. newline newline