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

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Abstract

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.

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Acknowledgments

The authors are grateful to all participating psychiatrists and medical staff who were involved in the metabolic monitoring program.

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    Authors and Affiliations

    1. Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Hospital of Cery, Lausanne University Hospital, 1008, Prilly, Switzerland

      Frederik Vandenberghe, Eva Choong & Chin B. Eap

    2. Division of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, Lausanne, Switzerland

      Monia Guidi & Chantal Csajka

    3. Service of Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, 1008, Prilly, Switzerland

      Armin von Gunten

    4. Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, 1008, Prilly, Switzerland

      Philippe Conus

    5. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland

      Monia Guidi, Chantal Csajka & Chin B. Eap

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    Funding

    This work has been funded in part by the Swiss National Research Foundation (CBE and PC: 320030-120686 and 324730-144064).

    Author disclosure information

    In the previous 3 years, Dr. Chin B. Eap has received research support from Takeda Pharmaceutical Company, and the Roche Organ Transplantation Research Foundation (#152358701). During this time, he has also received honoraria for conferences or for teaching continuing medical education (CME) courses from Advisis, Astra Zeneca, Essex Chemie, Lundbeck, Merck Sharp & Dohme, Sandoz, and Vifor-Pharma. Also in the previous 3 years, Dr. Armin von Gunten has received honoraria for conference or workshop participation from Vifor and Bayer Sheringer. Frederik Vandenberghe, Monia Guidi, Eva Choong, Philippe Conus, and Chantal Csajka declare no conflicts of interest in relation to the content of this study.

    Author contributions

    Professor Chin B. Eap had full access to all of the study data, and takes responsibility for the integrity of the data and accuracy of the data analysis.

    Chin B. Eap contributed towards the study concept and design; Frederik Vandenberghe, Eva Choong, Armin von Gunten, and Philippe Conus contributed towards the acquisition of data; Frederik Vandenberghe, Monia Guidi, and Chantal Csajka completed the analysis and interpretation of data; Frederik Vandenberghe and Monia Guidi drafted the manuscript; all authors contributed towards the critical revision of the manuscript for important intellectual content; Monia Guidi and Frederik Vandenberghe undertook the statistical analysis; Chin B. Eap and Philippe Conus obtained funding for this study; and Armin von Gunten and Philippe Conus carried out administrative, technical, or material support.

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    C. Csajka and C. B. Eap contributed equally to this work.

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    Vandenberghe, F., Guidi, M., Choong, E. et al. Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort. Clin Pharmacokinet 54, 1259–1272 (2015). https://doi.org/10.1007/s40262-015-0289-8

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