Background: Due to high interindividual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics relies on clinical trial and error. This blind process of upward or downward clinical dose titration carries a risk of relapse and adverse effects in the treatment of schizophrenia. Using population pharmacokinetic methods, the authors therefore sought to predict plasma concentrations of risperidone (RIS) plus 9-hydroxyrisperidone (9-OH-RIS) before a dosage change.
Methods: Two plasma samples were collected at 2 separate given time points for the measurement of RIS and 9-OH-RIS concentrations from 50 patients with schizophrenia or schizoaffective disorder maintained on risperidone (mean ± SD age = 56 ± 15 years; 39 men). After an oral risperidone dose adjustment, a third sample was collected. The plasma concentration of the third sample was individually predicted in a blinded fashion with the 2 baseline plasma concentrations before dose adjustment and clinical and demographic information, using the mixed-effects model with NONMEM that was derived from the data of the Clinical Antipsychotic Trials in Intervention Effectiveness study.
Results: The mean (95% confidence interval) prediction errors (in ng/mL) were as low as 0.0 (−1.3 to 1.4) for RIS and 1.0 (−1.1 to 3.0) for 9-OH-RIS. The observed and predicted concentrations of RIS and 9-OH-RIS were highly correlated (r = 0.96, P < 0.0001 and r = 0.92, P < 0.0001, respectively).
Conclusions: Antipsychotic plasma concentrations can be predicted before risperidone dose adjustment. In light of the known relationship between plasma drug concentration, dopamine D2 receptor occupancy, and clinical effects, our results confirm that individualized dosing with the measurement of antipsychotic plasma concentrations has the potential for bedside clinical application.
*Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
†Geriatric Mental Health Program, Centre for Addiction and Mental Health, Toronto, Canada
‡Department of Psychiatry, Minami-Hanno Hospital, Saitama, Japan
§Department of Psychiatry, University of Toronto, Toronto, Canada
¶Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN.
Supported by Japan Research Foundation for Clinical Pharmacology, Tokyo, Japan (H.U.), Research Group for Schizophrenia, Tokyo, Japan (H.U.), Inokashira Hospital Research Grant (H.U.), Grant-in-Aid for Young Scientists-B from the Ministry of Education, Culture, Sports, Science and Technology, Tokyo, Japan (H.U.), Japanese Society of Clinical Neuropsychopharmacology, Tokyo, Japan (T.S.), Government of Canada Post-Doctoral Research Fellowships, Ottawa, Canada (T.S.), Kanae Foundation, Tokyo, Japan (T.S.), Mochida Memorial Foundation, Tokyo, Japan (T.S.), the Indiana CTSI, Indianapolis, IN (R.R.B.), and Centre for Addiction and Mental Health, Toronto, Canada (R.R.B.).
Dr Uchida has received speaker's honoraria from Janssen Pharmaceutical within the past 3 years. Dr Watanabe has received grants from Janssen Pharmaceutical within the past 3 years. Dr Mimura has received speaker's honoraria from Janssen Pharmaceutical within the past 3 years. Other authors have no conflicts of interest to disclose.
Correspondence: Hiroyuki Uchida, MD, PhD, Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan (e-mail: firstname.lastname@example.org).
Received November 2, 2011
Accepted December 28, 2011