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Modelling of the effect of carbamazepine on the pharmacokinetics of risperidone in psychotic patients of different phenotypes

Vermeulen, An and Piotrovsky, Vladimir

Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica N.V.

Introduction: Risperidone (RIS) is a well-known and widely used atypical antipsychotic drug, on the market for almost a decade now.

RIS is mainly metabolised by CYP2D6 to the active metabolite 9-hydroxy-risperidone. The sum of RIS and 9-hydroxy-risperidone constitutes the active antipsychotic entity or the ‘active moiety’ (AM). Since the activity of CYP2D6 is subject to genetic polymorphism, the population is divided in poor, intermediate and extensive metabolisers.

Besides being used to treat schizophrenia, RIS’ value for the treatment of other diseases like bipolar mania either as add-on therapy to the currently used mood stabilizers or as monotherapy has been investigated. Carbamazepine, one of these mood stabilizers, is well-known to induce the activity of several cytochromes, and has a profound effect on the pharmacokinetics of RIS and AM.

Objectives: The objectives of the current population pharmacokinetic analysis were:

  • to model the pharmacokinetics of RIS in subjects of different phenotypes;
  • to compare two methods of phenotyping: one based on the metabolic ratio (AM to RIS clearance) and another one using the mixture model for RIS embedded in the population PK model;
  • to model the effect of carbamazepine on the pharmacokinetics of RIS in each of these phenotypes.

Methods and results: A two-compartment disposition model with zero-order followed by first-order absorption, and lag-time was implemented for both RIS and AM. It was fitted to the data of several clinical trials using NONMEM software, and individual empirical Bayes estimates of basic PK parameters were obtained. Individual metabolic ratios were calculated as CLAM/CLRIS where CLAM and CLRIS are AM and RIS clearance, respectively. The distribution of metabolic ratios was examined and each subject was assigned to one of the phenotypes. The individually assigned phenotype was included in the data set as a covariate, and the covariate model was built using the conventional method. Carbamazepine co-administration was demonstrated to have a significant impact on the apparent bioavailability fraction.

An alternative approach consisted of fitting a common model for RIS and 9-hydroxy-risperidone to plasma concentration-time data of both compounds. The model incorporated a mixture for the apparent RIS fraction converted into the metabolite. In this model, carbamazepine was shown to affect this fraction.