Original Contributions

Pharmacogenetic Study on Risperidone Long-Acting Injection

Influence of Cytochrome P450 2D6 and Pregnane X Receptor on Risperidone Exposure and Drug-Induced Side-Effects

Choong, Eva PhD^*; Polari, Andrea MD^†; Kamdem, Rigobert Hervais MD^‡; Gervasoni, Nicola MD^§; Spisla, Caesar MD^∥; Sirot, Eveline Jaquenoud PhD^¶; Bickel, Graziella Giacometti MD^‡; Bondolfi, Guido MD^§; Conus, Philippe MD^†; Eap, Chin B. PhD^*#

Author Information

From the *Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, University Hospital Centre and University of Lausanne; and †Service de Psychiatrie Générale, Département de Psychiatrie-CHUV, Hôpital de Cery, Prilly; ‡Fribourg Mental Health Network, Fribourg; §Department of Mental Health and Psychiatry, University Hospital of Geneva, Geneva; ∥Psychiatrische Dienste Aargau AG, Aarau; ¶Psychiatrische Dienste Aargau AG, mediQ, Klinik Königsfelden, Brugg; and #School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.

Received September 15, 2011; accepted after revision October 24, 2012.

Reprints: Chin B. Eap, PhD, Hôpital de Cery, 1008 Prilly, Lausanne, Switzerland (e-mail: [email protected]).

This work has been funded in part by the Swiss National Research Foundation (no. 320030-120686) and by a nonrestricted educational grant by Janssen-Cilag Switzerland. The funding sources had no role in the writing of the manuscript or in the decision to submit it for publication.

Journal of Clinical Psychopharmacology 33(3):p 289-298, June 2013. | DOI: 10.1097/JCP.0b013e31828f62cd

Abstract

Risperidone is metabolized by polymorphic enzymes, and a large variability in plasma concentration and therapeutic response is observed. Risperidone long-acting injection (RLAI) avoids the first-pass effect, and little is known about the influence of gene polymorphisms involved in its pharmacokinetics. The influence on plasma concentrations of risperidone (RIS), its metabolite 9-hydroxy-risperidone, and on adverse effects were investigated for polymorphisms of cytochrome P450 2D6 (CYP2D6) (*3, *4, *5, *6), CYP3A (CYP3A4*1B, CYP3A4 rs4646437, CYP3A5*3, CYP3A7*1C), ABCB1 (1236C>T, 2677G>T, 3435C>T), NR1/2 coding for pregnane X receptor (rs1523130, rs2472677, rs7643645), and for CYP3A activity measured by a phenotyping test. Forty-two patients with at least 4 consecutive unchanged doses of RLAI were included in a multicenter cross-sectional study. A 55% lower dose-adjusted plasma levels of RIS were observed for CYP2D6 ultrarapid metabolizers (n = 5) as compared with CYP2D6 intermediate metabolizers (P < 0.007). NR1/2 polymorphism (rs7643645A>G) influenced RIS exposure with a 2.8-fold lower active moiety (P = 0.031) in GG compared with the AA genotype. This was confirmed in a second independent cohort (n = 16). Furthermore, high-density lipoprotein cholesterol was positively correlated with CYP3A activity (P = 0.01), and the NR1/2 (rs2472677) polymorphism was associated with different adverse effects including prolactin plasma levels adjusted for age and sex. In conclusion, our results confirmed the influence of CYP2D6 genotype on plasma levels of RIS. This is the first report on the influence of NR1/2 polymorphisms on RLAI exposure and on drug-induced adverse effects. These results should be validated in larger cohorts.