Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment. Issue 6 (December 2016)

• Record Type: Journal Article
• Authors: Schoretsanitis, Georgios; Haen, Ekkehard; Gründer, Gerhard; Stegmann, Benedikt; Schruers, Koen R. J.; Hiemke, Christoph; Lammertz, Sarah E.; Paulzen, Michael
• Is Part Of: Journal of clinical psychopharmacology. Volume 36:Issue 6(2016)
• Publication Date: 2016-12
• Subjects: therapeutic drug monitoring -- risperidone -- carbamazepine -- valproic acid -- lamotrigine cytochrome P450 -- interaction -- pharmacokinetics; Psychopharmacology -- Periodicals; Psychopharmacology -- Periodicals; Psychopharmacologie -- Périodiques; Psychopharmacology; Periodicals; 615.78
• DOI: 10.1097/JCP.0000000000000601
• Languages: English
• ISSNs: 0271-0749

Abstract

Abstract : Background: The combination of anticonvulsant mood stabilizers with antipsychotic drugs may lead to clinically relevant drug-drug interactions. The objective of the study was to identify pharmacokinetic interactions of different mood stabilizers on the metabolism of risperidone (RIS) under natural conditions. Methods: A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxy-RIS (9-OH-RIS) of 1, 584 adult patients was analyzed. Four groups (n = 1, 072) were compared: a control group without a potentially cytochrome interacting comedication (R0, n = 852), a group comedicated with valproate (VPA) (RVPA, n = 153), a group comedicated with lamotrigine (LMT) (RLMT, n = 46), and a group under concomitant medication with carbamazepine (CBZ) (RCBZ, n = 21). Dose-adjusted plasma concentrations (C/D ratio) for RIS, 9-OH-RIS and active moiety (AM) (RIS + 9-OH-RIS), as well as metabolic ratios (RIS/9-OH-RIS) were computed. Results: Groups did not differ with regard to the daily dosage ( P = 0.46). Differences were detected for the distributions of the C/D ratios for RIS, 9-OH-RIS and AM ( P = 0.003, P < 0.001 and P < 0.001, respectively). Differences remained significant after conducting a Bonferroni correction ( P = 0.0125). Pairwise comparisons of the concomitant medication groups with the control group revealed significant differences; RIS C/D ratios were significantly higher in the VPA and the LMT group than in the control group ( P = 0.013; P = 0.021). However, these differences did not remain significant after Bonferroni correction. In contrast, CBZ-treated patients showed lower dose-adjusted plasma concentrations of 9-OH-RIS ( P < 0.001) as well as the AM ( P < 0.001) than the control group; this difference survived the Bonferroni correction. Conclusions: The data give evidence for pharmacokinetic interactions between RIS and different anticonvulsant mood stabilizers. Carbamazepine decreased serum concentrations of 9-OH-RIS and the AM when compared with the control group. In case of VPA and LMT, findings were less significant; hints for a weak RIS metabolism inhibition by LMT of unclear clinical significance were found.