Population Pharmacokinetic Analysis Of Risperidone And Its Metabolite And Evaluation Of Effect Of Covariates On Pk Parameters

Abstract

AIMS
To characterize pharmacokinetic (PK) variability of risperidone and 9-OH risperidone using sparse sampling and to evaluate the effect of covariates on PK parameters.
METHODS
PK analysis used plasma samples collected from the Clinical Anti-psychotic Trials of Intervention Effectiveness. A nonlinear mixed-effects model was developed using NONMEM to describe simultaneously the risperidone and 9-OH risperidone concentration–time profile. Covariate effects on risperidone and 9-OH risperidone PK parameters were assessed, including age, weight, sex, smoking status, race and concomitant medications.
RESULTS
PK samples comprised risperidone and 9-OH risperidone concentrations from 20 subjects that were available for analysis. Ages ranged from 18 to 93 years. Population PK sub models for both risperidone and 9-OH risperidone with first-order absorption were selected to describe the concentration–time profile of risperidone and 9-OH risperidone. A mixture model was incorporated with risperidone clearance (CL) separately estimated for three subpopulations [poor metabolizer (PM), extensive metabolizer (EM) and intermediate metabolizer (IM)]. Age significantly affected 9-OH risperidone clearance. Population parameter estimates for CL in PM, IM and EM were 12.9, 36 and 65.4 l h-1 and parameter estimates for risperidone half-life in PM, IM and EM were 25, 8.5 and 4.7 h, respectively.
CONCLUSIONS
A one-compartment mixture model with first-order absorption adequately described the risperidone and 9-OH risperidone concentrations. Age was identified as a significant covariate on 9-OH risperidone clearance in this study.