serval:BIB_594496D78157
Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort.
10.1007/s40262-015-0289-8
000365716700006
26129906
Vandenberghe
F.
author
Guidi
M.
author
Choong
E.
author
von Gunten
A.
author
Conus
P.
author
Csajka
C.
co-last author
Eap
C.B.
co-last author
article
2015
Clinical Pharmacokinetics
1179-1926
0312-5963
journal
54
12
1259-1272
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.
Adult
Antipsychotic Agents/administration & dosage
Antipsychotic Agents/adverse effects
Cross-Sectional Studies
Cytochrome P-450 CYP2D6/genetics
Cytochrome P-450 CYP2D6/metabolism
Female
Humans
Longitudinal Studies
Male
Mental Disorders/drug therapy
Mental Disorders/genetics
Models, Biological
Paliperidone Palmitate/blood
Paliperidone Palmitate/chemistry
Polymorphism, Genetic
Prolactin/metabolism
Retrospective Studies
Risperidone/administration & dosage
Risperidone/adverse effects
eng
60_published
peer-reviewed
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
University of Lausanne
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