Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study

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 Antipsychotic 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 1236 risperidone and 1236 9-OH risperidone concentrations from 490 subjects that were available for analysis. Ages ranged from 18 to 93 years. Population PK submodels 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.

Figures

Figure 1

Frequency histogram showing the age (a) and weight (b) distribution for all subjects in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)-SZ and CATIE-AD studies

Figure 2

Frequency histogram showing the sampling distribution for risperidone sampling measurements in Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)-SZ (a) and CATIE-AD (b) studies. The abscissa is broken into 1-h bins. The ordinate is the proportion of samples taken in each interval

Figure 3

Base population pharmacokinetic model structure for risperidone and 9-OH risperidone, KF is the fraction of risperidone to 9-OH risperidone

Figure 4

Diagnostic plots of final pharmacokinetic model. (a,e) Plot of observed concentrations vs. population predicted risperidone (a) and 9-OH risperidone (e) concentrations. Dots represent individual data points; solid line represents the unity line and dashed line represents the smooth line. (b,f) Plot of observed concentrations vs. individual population predicted risperidone (b) and 9-OH risperidone (f) concentrations. Dots represent individual data points; solid line represents the unity line and dashed line represents the smooth line. (c,g) Plot of weighted residual error (WRES) vs. population predicted risperidone (c) and 9-OH risperidone (g) concentrations. Dashed line represents the smooth line. (d,h) Plot of WRES vs. time after most recent dose for risperidone (d) and 9-OH risperidone (h). Dashed line represents the smooth line

Figure 5

9-OH risperidone clearance (CLM) vs. age. Line represents the smooth line

Figure 6

Histogram of risperidone clearance estimates (CL)