Clozapine dosages and plasma drug concentrations

Steady-state plasma concentrations of clozapine and its metabolites, desmethylclozapine and clozapine-N-oxide, were measured in 162 Taiwanese patients with refractory schizophrenia. The daily doses of clozapine ranged from 100 to 900 mg, with a mean value of 379.5 ± 142.2 mg. A dosage of 400 mg/day or lower was used for most patients (n = 131, 81%). Plasma concentrations of clozapine and its two major metabolites were measured using high performance liquid chromatography with ultraviolet detection. The mean plasma clozapine concentration was 566.9 ± 398.8 ng/mL. The plasma concentrations of desmethylclozapine and clozapine-N-oxide were 46% and 16% of the concentration of the parent drug, respectively. We used an approximate rule that each 100 mg/day dose results in about 150 ng/mL plasma clozapine. This value is about 30% to 50% higher than that reported in Caucasians. The suggested therapeutic plasma clozapine concentration range of 300 to 700 ng/mL can be achieved with a dose range of 200 to 500 mg/day in most Taiwanese patients. Dose-dependent plasma clozapine concentrations were found. The interpatient variation was up to 12-fold in patients receiving the same dose, eg, 400 mg/day (n = 62). In four of these patients, the plasma drug concentrations were very high (1,446 ± 114 ng/mL). The application of therapeutic drug monitoring in clozapine-treated patients with refractory schizophrenia is important, not only in dose adjustment, prediction of severe side effects such as seizures, and exploration of drug interactions, but also in the effective use of this expensive drug.