Using therapeutic drug monitoring to personalize clozapine dosing in Asians

This narrative review on clozapine blood levels or therapeutic drug monitoring (TDM) includes sections focused on drug clearance and TDM, personalized dosing with TDM, clinical applications of TDM in Asians, and areas needing further study. Asian patients need half the clozapine dose (D) used in the United States to get the same blood concentrations (C). The concentration-to-dose (C/D) ratio measures drug clearance. In the United States, the average clozapine patient usually needs from 300 to 600 mg/day to reach 350 ng/mL. US male smokers reach this therapeutic C with a D of 600 mg/day (C/D ratio of 0.60 = 600/350), whereas US female nonsmokers usually need a D of 300 mg/day (C/D ratio of 1.17 = 300/350). While in the United States, average CLO C/D ratios typically are 0.6-1.2 ng/mL per mg/day, in Asian populations they range from 1.20 in male smokers to 2.40 in female smokers, requiring Ds of 300 to 150 mg/day to obtain 350 ng/mL. Asian patients can become clozapine poor metabolizers (PMs), needing very low Ds (50-150 mg/day) to get therapeutic Cs, by taking inhibitors (fluvoxamine, oral contraceptives and valproic acid), due to obesity, or during inflammations with systemic effects. In 573 Asian patients from five samples, around 1% were PMs due to taking inhibitors, 1% due to inflammation, 1% due to obesity, and 7% were potential genetic PMs. The potential genetic PMs ranged between 3% and 13%, but this prevalence will have to be better established in future studies including genetic testing for possible CYP1A2 mutations, which may explain PM status.