Journal
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 41, Issue 2, Pages 289-298Publisher
ELSEVIER
DOI: 10.1016/j.ejps.2010.06.016
Keywords
Risperidone; 9-Hydroxyrisperidone enantiomers; Population pharmacokinetics; CYP2D6 genotype; Extrapyramidal symptoms
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Funding
- Slovenian Research Agency (ARRS) [P1-0189, P1-0170]
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The objective of this prospective study was to characterize the metabolism of risperidone to (+)- and (-)-9-hydroxyrisperidone in vivo and to evaluate the influence of CYP2D6 genotype. A population pharmacokinetic modeling approach was used to estimate the interindividual variability of the pharmacokinetic parameters in 50 hospitalized patients with acute episode of schizophrenia. CYP2D6 genotype remarkably influenced the formation clearances of the risperidone metabolites, while creatinine clearance was related to the plasma clearance of 9-hydroxyrisperidone. CYP2D6 genotype was also associated with the average plasma concentration of risperidone active moiety (a sum of all three active compounds). In comparison to the patients with CYP2D6*1/*1 genotype, average steady-state plasma concentration of risperidone active moiety was 3.3- and 1.6-fold higher in poor metabolizers (both alleles nonfunctional; CYP2D6*3 or *4) and intermediate metabolizers (one nonfunctional allele and one allele for diminished enzyme activity: CYP2D6*10 or *41), respectively. Additionally, average plasma concentration of risperidone active moiety was higher in the patients with dystonia (p = 0.0066) and parkinsonism (p = 0.046). The results of this study imply the potential role of CYP2D6 genotyping in personalizing risperidone therapy in patients with schizophrenia to reduce the incidence of adverse extrapyramidal symptoms. (C) 2010 Elsevier B.V. All rights reserved.
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