Population Pharmacokinetics of Risperidone in Patients with Acute Schizophrenia
I. Locatelli(1), M. Kastelic(2), J. Koprivsek(3), B. Kores-Plesnicar(3), A. Mrhar(1), V. Dolzan(2), I. Grabnar(1)
(1)Chair of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Slovenia; (2)Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Slovenia; (3)Department of Psychiatry, University Clinical Centre Maribor, Maribor, Slovenia
Objectives: Atypical antipsychotic risperidone (RISP) undergoes extensive CYP2D6 and CYP3A4 catalyzed hydroxylation to active 9-hydroxyrisperidone enantiomers (9OH-RISP) . Large interindividual variability in formation rate of 9OH-RISP was observed , however, stereoselectivity of this metabolic reaction has not been investigated in vivo. In this study population pharmacokinetic model of RISP metabolism to 9OH-RISP enantiomers was developed to evaluate the influence of CYP2D6 genetic polymorphism on RISP first-pass metabolism (Fp) and formation clearances of the 9OH-RISP enantiomers.
Methods: Hospitalized patients in acute phase of schizophrenia treatment with risperidone tablets were included in the study. Two blood samples approximating trough and peak RISP concentrations were drawn on day 8 of the treatment. Plasma concentrations of RISP and 9OH-RISP enantiomers were determined using validated HPLC method with electrochemical detection. The patients were CYP2D6 genotyped. NONMEM was used for the pharmacokinetic analysis. The model consisted of three compartments, one for each of the investigated compounds. Additionally, depot compartment, Fp metabolism to 9OH-RISP, and interconversion of 9OH-RISP enantiomers were included. The model was expressed in terms of appropriate differential equations using ADVAN6. FOCEI was used for parameter estimation.
Results: 50 patients contributed to 296 concentration data. Inclusion of 9OH-RISP interconversion clearance (Qm = 25 L/h) in the model resulted in significant decrease of objective function value (p<0.001). Formation of (-)-9OH-RISP from RISP was found negligible, while formation clearance of (+)-9OH-RISP (CLf+) was estimated at 17 L/h. Interindividual variability of this parameter was large (CV = 90%) and was reduced to 55%, when CYP2D6 genotype was included as covariate. The patients with two non-functional CYP2D6 alleles have 11.8 fold lower CLf+ compared to the patients with wild type CYP2D6 alleles. Volume of distribution was set equal for all three compounds and was estimated at 1.7 L/kg. Plasma clearance of 9OH-RISP was set equal for both enantiomers and was 7.4 L/h.
Conclusions: This model demonstrates that in vivo formation of 9OH-RISP from RISP is stereoselective. The main metabolite of RISP is (+) 9OH-RISP. This formation is largely dependent on CYP2D6 activity. (-)-9OH-RISP is mainly formed from the (+) enantiomer.
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 Vermeulen A, Piotrovsky V, and Ludwig EA. Population pharmacokinetics of risperidone and 9-hydroxyrisperidone in patients with acute episodes associated with bipolar I disorder. J Pharmacokinet Pharmacodyn, 2007; 34: 183-206.