Age and Sex Impact Clozapine Plasma Concentrations in Inpatients and Outpatients With Schizophrenia Zahinoor Ismail, B.M.Sc., M.D., F.R.C.P.C., Alette M. Wessels, Ph.D., Hiroyuki Uchida, M.D., Ph.D., Wenzie Ng, B.Sc., M.Pharm., David C. Mamo, M.D., M.Sc., F.R.C.P.C., Tarek K. Rajji, M.D., F.R.C.P.C., Bruce G. Pollock, M.D., Ph.D., F.R.C.P.C., Benoit H. Mulsant, M.D., M.S., F.R.C.P.C., Robert R. Bies, Pharm.D., Ph.D. Background: Although clozapine is primarily used in a younger to mid-life popula- tion of patients with psychosis, there are limited data on the clinical pharmacology of clozapine later in life. The objective of this study was to assess the magnitude and vari- ability of plasma concentrations of clozapine and norclozapine across the lifespan in a real-world clinical setting. Design: A population pharmacokinetic study using nonlinear mixed effect modeling (NONMEM). Age, sex, height, weight, and dosage formulation were covariates. Setting: Inpatients and outpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007. Participants: Patients ranging in ages from 11 to 79 with schizophrenia spectrum disorders and prescribed clozapine (Clozaril). Measurements: A total of 1142 plasma clozapine and nor- clozapine concentrations (2,284 concentration measurements) from 391 patients with schizophrenia spectrum disorder. Results: A one-compartment model with first- order absorption and elimination best described the data. The population predicted clearance of clozapine for females was 27.1 L/h (SE 11.1%) and 36.7 L/h (SE 9.7%) for males. For norclozapine, clearance in females was 48.6 L/h (SE 10.8%) and 63.1 L/h (SE 9.3%) in males. The only covariates with a significant effect on clearance were age and sex: clearance for both parent and metabolite decreased exponentially with age at least 39 years. Conclusions: Decreased clearance of clozapine and norcloza- pine with age results in increased blood concentrations and, hence, the potential for adverse drug reactions. These findings have particular clinical relevance for the Received July 12, 2010; revised January 4, 2011; accepted January 6, 2011. ZI and AMW contributed equally to this study. From the Centre for Addiction and Mental Health, Geriatric Mental Health Program, Toronto, Ontario, Canada (ZI, HU, DCM, TKR, BGP, BHM, RRB); Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (ZI, DCM, TKR, BGP, BHM); Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada (ZI); Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (AMW, RRB), Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan (HU); School of Pharmacy, University of London, London, England (WN). Send correspondence and reprint requests to Alette M Wessels, Ph.D., Division of Clinical Pharmacology, Wishard Memorial Hospital, 1001 West 10th St, WD Meyers Building, W7123, Indianapolis, IN 46202. e-mail: awessels@iupui.edu c  2011 American Association for Geriatric Psychiatry DOI: 10.1097/JGP.0b013e3182118318 Copyright © American Association for Geriatric Psychiatry. Unauthorized reproduction of this article is prohibited. Am J Geriatr Psychiatry 20:1, January 2012 53