Do asian patients require only half of the clozapine dose prescribed for caucasians? A critical overview

• Authors: Jose De Leon, University of the Basque Country, Vitoria, Spain; Anto P. Rajkumar, University of Nottingham; Arun R. Kaithi, Hazelwood Center; Georgios Schoretsanitis, The Zucker Hillside Hospital; John M. Kane, The Zucker Hillside Hospital; Chuan-Yue Wang, Capital Medical University, Beijing, China; Yilang Tang, Emory University; Shih-Ku Lin, Taipei Medical University, Taipei, Taiwan; Kyung Sue Hong, Sungkyunkwan University; Saeed Farooq, Keele University; Chee H. Ng, University of Melbourne; Can-Jun Ruan, Capital Medical University, Beijing, China; Chittaranjan Andrade, National Institute of Mental Health and Neuro Sciences
• Journal Title: Indian Journal of Psychological Medicine
• Volume: Volume 42, Number 1
• Publisher: SAGE Publications (on behalf of the Indian Psychiatric Society, South Zonal Branch) | 2020-01-01, Pages 4-10
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.4103/IJPSYM.IJPSYM_379_19
• Subjects: Biology, Neuroscience; Psychology, Social; Biology, Molecular; Health Sciences, Medicine and Surgery
• Keywords: Asian continental ancestry group/genetics; CYP1A2; India; blood; clozapine; drug labeling; pharmacokinetics; sex; smoking

Abstract

Since 1997, studies have found that Asians need lower clozapine doses than Caucasians. Caucasians with average clozapine metabolism may need from 300 to 600 mg/day to reach the therapeutic range (350 ng/ml). Thus, serum clozapine concentration-to-dose (C/D) ratios typically range between 0.60 (male smokers) and 1.20 (female non-smokers). A 2019 systematic review of clozapine levels demonstrated weighted mean C/D ratios of 1.57 in 876 East Asians and 1.07 in 1147 Caucasians (P <.001). In Asian countries, average clozapine doses are lower than 300 mg/day. After sex and smoking stratification in 5 Asian samples with clozapine concentrations, the clozapine dose required to reach 350 ng/ml in female non-smokers ranged from 145 to 189 mg/day and in male smokers, from 259 to 294 mg/day. Thus, in Asian patients with average metabolism (with no inducers other than smoking, with no inhibitors, and in the absence of extreme obesity), the dose needed for clinical response may range between 150 mg/day for female non-smokers to 300 mg/day for male smokers. Clozapine levels may help personalize dosing in clozapine poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Asian PMs may need very low doses (50-150 mg/day) to obtain therapeutic concentrations. About 10% (range 2-13%) of Asians are genetic PM cases. Other PMs are patients taking CYP1A2 inhibitors such as fluvoxamine, oral contraceptives, and valproate. Temporary clozapine PM status may occur during severe systemic infections/inflammations with fever and C-reactive protein (CRP) elevations. Asian UMs include patients taking potent inducers such as phenytoin, and rarely, valproate.