Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort.
- Vandenberghe F Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Hospital of Cery, Lausanne University Hospital, 1008, Prilly, Switzerland.
- Guidi M Division of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, Lausanne, Switzerland.
- Choong E Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Hospital of Cery, Lausanne University Hospital, 1008, Prilly, Switzerland.
- von Gunten A Service of Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, 1008, Prilly, Switzerland.
- Conus P Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, 1008, Prilly, Switzerland.
- Csajka C Division of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, Lausanne, Switzerland.
- Eap CB Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Hospital of Cery, Lausanne University Hospital, 1008, Prilly, Switzerland. chin.eap@chuv.ch.
- 2015-07-02
Published in:
- Clinical pharmacokinetics. - 2015
Adult
Antipsychotic Agents
Cross-Sectional Studies
Cytochrome P-450 CYP2D6
Female
Humans
Longitudinal Studies
Male
Mental Disorders
Models, Biological
Paliperidone Palmitate
Polymorphism, Genetic
Prolactin
Retrospective Studies
Risperidone
English
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.
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1007/s40262-015-0289-8
- PMID 26129906
- Persistent URL
- https://sonar.ch/global/documents/181619
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