Clozapine Metabolism in East Asians and Caucasians

Abstract

Purpose/Background In clozapine therapeutic drug monitoring (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.

Clozapine is strongly associated with the risk of pneumonia and inflammation

“…Therefore, smokers tend to have serum concentration values that are approximately 0.80 that of non-smokers when using the same clozapine dose. 2 Conversely, oestrogens have inhibitory effects on CYP1A2 activity. Male patients, then, tend to have serum concentration values that are approximately 0.86 that of females when using the same clozapine dose.…”

“…Male patients, then, tend to have serum concentration values that are approximately 0.86 that of females when using the same clozapine dose. 2 Co-medication with inducers such as carbamazepine, phenytoin or rifampicin increase clozapine metabolism and decrease clozapine levels. The most important inhibitors of clozapine metabolism are ciprofloxacin, oral contraceptives, fluvoxamine and caffeine in high doses.…”

“…6 Until a better definition of clozapine PMs in non-Asians is established, we recommend considering non-Asian clozapine PMs as those who reach 350 ng/mL with clozapine doses <300 mg/day. 2…”

“…In summary, data from (1) the lamotrigine literature; (2) the clinical experience of the authors; (3) the review of TDM studies from the US, Europe and Asia; and (4) VigiBase has been used to reframe the myocarditis debate. Myocarditis is extremely rare in non-Australian countries and can be avoided by slow, personalised titration.…”

Do Asians Patients Require Only Half of the Clozapine Dose Prescribed for Caucasians? A Critical Review

“…A recent study comparing Chinese (N = 126, from Beijing) to a previously published Caucasian Italian outpatient sample (N = 152) also reported a clozapine concentration/dose (C/D) ratio of 1.57, higher among the Asian group. [8] C l o z a p i n e m e t a b o l i s m h a s b e e n e l u c i d a t e d and involves mainly hepatic cytochrome P450 CYP1A2. [9] Although other CYPs are involved in clozapine metabolism, CYP1A2 remains the predominant metabolic pathway.…”