Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort

• Published in: Clinical pharmacokinetics 2015-12, Vol.54 (12), p.1259-1272
• Main Authors: Vandenberghe, Frederik, Guidi, Monia, Choong, Eva, von Gunten, Armin, Conus, Philippe, Csajka, Chantal, Eap, Chin B.
• Format: Article
• Language: English
• Subjects: Adult; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - adverse effects; Antipsychotic Agents - blood; Antipsychotic Agents - pharmacokinetics; Cross-Sectional Studies; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Female; Humans; Internal Medicine; Longitudinal Studies; Male; Medicine; Medicine & Public Health; Mental Disorders - drug therapy; Mental Disorders - genetics; Mental Disorders - metabolism; Models, Biological; Original Research Article; Paliperidone Palmitate - blood; Paliperidone Palmitate - chemistry; Paliperidone Palmitate - pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Polymorphism, Genetic; Prolactin - metabolism; Retrospective Studies; Risperidone - administration & dosage; Risperidone - adverse effects; Risperidone - blood; Risperidone - pharmacokinetics
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-015-0289-8

Background High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, may lead to suboptimal drug concentration. Objective Using a population pharmacokinetic approach, we aimed to characterize the genetic and non-genetic sources of variability affecting risperidone and 9-hydroxyrisperidone pharmacokinetics, and relate them to common side effects. Methods Overall, 150 psychiatric patients (178 observations) treated with risperidone were genotyped for common polymorphisms in NR1/2 , POR , PPARα , ABCB1 , CYP2D6 and CYP3A genes. Plasma risperidone and 9-hydroxyrisperidone were measured, and clinical data and common clinical chemistry parameters were collected. Drug and metabolite concentrations were analyzed using non-linear mixed effect modeling (NONMEM ® ). Correlations between trough concentrations of the active moiety (risperidone plus 9-hydroxyrisperidone) and common side effects were assessed using logistic regression and linear mixed modeling. Results The cytochrome P450 (CYP) 2D6 phenotype explained 52 % of interindividual variability in risperidone pharmacokinetics. The area under the concentration–time curve (AUC) of the active moiety was found to be 28 % higher in CYP2D6 poor metabolizers compared with intermediate, extensive and ultrarapid metabolizers. No other genetic markers were found to significantly affect risperidone concentrations. 9-hydroxyrisperidone elimination was decreased by 26 % with doubling of age. A correlation between trough predicted concentration of the active moiety and neurologic symptoms was found ( p   =  0.03), suggesting that a concentration >40 ng/mL should be targeted only in cases of insufficient, or absence of, response. Conclusions Genetic polymorphisms of CYP2D6 play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a personalized dosage adjustment during risperidone treatment.