M. Guidi (1) (2), F. Vandenberghe (3), E. Choong (3), T. Buclin (1), C.B. Eap (2) (3), C. Csajka (1) (2)
(1) Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland; (2) School of Pharmacy, Department of Pharmaceutical Sciences, University of Geneva and Lausanne, Geneva Switzerland; (3) Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, University Hospital Lausanne, Prilly-Lausanne, Switzerland.
Objectives: A therapeutic range has been proposed for risperidone (RISP) and 9-hydroxy-risperidone (9OHRISP). Their pharmacokinetics is subject to a high inter-variability, mainly due to polymorphic enzymes, which can contribute to the variability of treatment response and sides effects. The aim of this analysis was to characterize the population pharmacokinetics of RISP and 9OHRISP, to test the influence of genetic polymorphism along with non-genetic factors on drug and metabolite levels and to compare the active moiety (RISP + 9OHRISP) expositions between the metabolic groups.
Methods: A one-compartment model with first-order absorption and elimination was used to describe the pharmacokinetics of both RISP and 9OHRISP, with linear metabolisation from drug to metabolite (NONMEM®). Total 9OHRISP (CL9OHRISP) clearance, drug over metabolite concentrations ratio (D/M), drug and metabolite AUC0-24 were derived from the model. The AUC0-24 of the active moiety was obtained by summing RISP and 9OHRISP AUC0-24. Co-administered drugs and demographic, clinical variables, CYP2D6 phenotoypes and genetic polymorphisms in CYP3A4 rs4646437 C>T, CYP3A4*1B, CYP3A5*3, CYP3A7*1C, POR rs1057868 (*28 C>T), PXR rs7643645, PXR rs1523130 and PXR rs2472677 were tested as covariates.
Results: A total of 144 concentrations of both RISP and 9OHRISP were available from 127 patients. Among all the evaluated covariates, CYP2D6 phenotype had the most significant impact on both drug clearance (CLRISP) and metabolism (k23) rate constant. CLRISP was also affected by AGE. These covariates explain altogether 48% and 66% of the interpatient variability in CLRISPand k23, respectively. No difference between CYP2D6 intermediate (IM), extensive (EM) and ultra (UM) metabolizers were observed. CLRISP and D/M ratio were estimated to be respectively 4.8 L/h and 4.2 in PM and 22.9 L/h and 0.34 in IM/EM/UM patients. The AUC0-24 of the active moiety derived by simulation of the final model was 1112 ng•h/ml (90%PI: 503-1994 ng•h/ml) for the CYP2D6 PM vs. 753 ng•h/ml (90%PI: 329-1423 ng•h/ml) for the IM/EM/UM (p< 0.001).
Conclusions: CYP2D6 polymorphism accounts for the majority of the variation in risperidone and its active metabolite drug levels. The significant difference found in the active moiety exposure between poor and intermediate or good metabolizers might explain reported higher rates of side-effects and drop-out in risperidone poor metabolizers [1].
References:
[1] de Leon, J., et al., The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry, 2005. 66(1): p. 15-27.
Reference: PAGE 21 (2012) Abstr 2502 [www.page-meeting.org/?abstract=2502]
Poster: CNS