Clozapine Metabolism in East Asians and Caucasians A Pilot Exploration of the Prevalence of Poor Metabolizers and a Systematic Review

Purpose/Background: In clozapine therapeutic drugmonitoring (TDM) studies, Chinese reached the same concentrations using half the dosage Caucasians use. Defining clozapine poor metabolizers (PMs) requires stratification by ethnicity, smoking, and sex. Methods/Procedures: After sex and smoking stratification in 129 Chinese inpatients (mean, 8.8 TDM samples per patient), we explored the association between the total concentration-dose (C/D) ratio and CYP1A2 (*1C, *1F, and *7) and CYP2C19 alleles (*2 and *3). A systematic literature review identified 22 clozapine TDM prior studies (13 in Caucasians and 7 in East Asians). Findings/Results: In our Chinese sample, the mean total clozapine C/D ratio (ng/mL per mg/d) was 1.96 for 22 male smokers, 2.07 for 5 female smokers, 2.47 for 36 male nonsmokers, and 2.95 for 66 female nonsmokers. CYP1A2*1C had no significant effects, and CYP1A2*1F had small effects. Five clozapine PMs (4%) needed low clozapine doses of 75 to 115 mg/d to get therapeutic concentrations. Using the same methodology in a published Italian sample, we found 5 PMs (3.3% of 152). In the systematic review, the clozapine C/D ratio (ng/mL per mg/d) was higher when comparing: (1) weighted mean values of 1.57 in 876 East Asians versus 1.07 in 1147 Caucasians and (2) ranks of 8 East Asians versus 13 Caucasian samples (P < 0.001). Implications/Conclusions: Future TDM studies need to further explore the frequency of clozapine PMs after sex and smoking stratification in East Asian and Caucasian patients. Compared with Caucasians, East Asians appear to have a clinically relevant decrease in clozapine clearance.