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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Risperidone metabolism is affected by blocking CYP2D6 and CYP3A4 (in CYP2D6 poor metabolizers) metabolizing enzymes.• Age affects risperidone disposition and renal function affects elimination of 9-hydroxy-risperidone (primary active metabolite). WHAT THIS STUDY ADDS• The detection of a systematic shift in estimated apparent clearance in the African-American population (it is not clear if there are biological or sociological contributors), and a shift in the clearance rate of risperidone based on concomitant administration of paroxetine, manifested as a change in assignment to a different metabolizer subpopulation group that may be primarily related to CYP2D6 metabolizer status. • The study shows an age-related decrement in 9-hydroxy-risperidone clearance across a wide range of ages.• Information on the nature of the pharmacokinetic variability with risperidone when used in a typical clinical patient population.• There are significant differences in the absolute values as well as the assignment to metabolizer status across race and concomitant paroxetine administration. AIMSTo characterize pharmacokinetic (PK) variability of risperidone and 9-OH risperidone using sparse sampling and to evaluate the effect of covariates on PK parameters. METHODSPK 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. RESULTSPK 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. CONCLUSIONSA 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.

Pharmacokinetic considerations in the treatment of hypertension in risperidone-medicated patients – thinking of clinically relevant CYP2D6 interactions

“…Furthermore, the distribution of the concentration-to-dose ratios showed an interesting pattern in the sense that patients in the amlodipine group were twice as likely to show C/D levels for RIS and the AM above the median as controls. Although pharmacokinetic parameters showed a high inter-individual variability, which has been detected in other studies as well (Balant-Gorgia et al, 1999;Cabaleiro et al, 2015;Feng et al, 2008), it should be noted that we observed no additional distribution differences regarding plasma concentrations and metabolic ratios of RIS as well as the C/Ds of the active metabolite of RIS (9-OH-RIS) between the groups. To our understanding, the findings presented herein imply a potential inhibiting effect of amlodipine most likely on the CYP3A4/5 mediated metabolism of RIS, leading to significantly higher median values of the concentration-to-dose ratios of RIS, 9-OH-RIS and the AM.…”

“…regarding the mean age of the different study groups, it appeared plausible that patients under antihypertensive therapy would be older. Consequently, we avoided stratifying for age despite the well-known effect of age on RIS metabolism (Feng et al, 2008). Although the size of the control group is remarkably bigger, we chose not to reduce our control group taking into account the extent of the skewness of the sample distribution.…”

Pharmacogenetics of antipsychotic treatment response and side effects

“…Pharmacokinetic analyses from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, by Feng et al [52] found that poor risperidone clearance was clearly associated with the PM status of CYP2D6 [53]. In this study, risperidone and 9-OH risperidone concentration data distinguished CYP2D6 polymorphism-related subpopulations.…”

Development of a Complex Parent-Metabolite Joint Population Pharmacokinetic Model

“…Joint pharmacokinetic (PK) modeling accounts for the uncertainties in the data and allows feedback from the metabolite data to the parent drug data to influence the estimation. Thus, more and more studies now use this approach (2)(3)(4). Also, joint modeling allows to correctly evaluate and predict the impact of drug-drug interactions, and in the case of reversible metabolic systems, it is the only way to properly assess covariate effects.…”

“…To solve the issue of structural identifiability, it is important to identify the parameters or "apparent" parameters that can be estimated (3), and for the sake of parameter interpretation or covariate analysis, it might be needed to make some assumptions on the parameters (e.g., fixing one parameter to a given value) (4). Also, instability during the estimation is likely to result in solutions at local minima which may lead to biased parameter estimates and potentially wrong conclusions.…”