title: Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort.
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.
authors.affiliation: Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Hospital of Cery, Lausanne University Hospital, 1008, Prilly, Switzerland.
authors.forename: Frederik
authors.initials: F
authors.lastname: Vandenberghe
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, Lausanne, Switzerland.|School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Monia
authors.initials: M
authors.lastname: Guidi
authors.affiliation: Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Hospital of Cery, Lausanne University Hospital, 1008, Prilly, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Choong
authors.affiliation: Service of Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, 1008, Prilly, Switzerland.
authors.forename: Armin
authors.initials: A
authors.lastname: von Gunten
authors.affiliation: Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, 1008, Prilly, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Conus
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, Lausanne, Switzerland.|School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Chantal
authors.initials: C
authors.lastname: Csajka
authors.affiliation: 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.|School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. chin.eap@chuv.ch.
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003430:Cross-Sectional Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D000068882:Paliperidone Palmitate / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D011110:Polymorphism, Genetic; D011388:Prolactin / Q000378:metabolism; D012189:Retrospective Studies; D018967:Risperidone / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D014150:Antipsychotic Agents; D011388:Prolactin; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate