Clozapine and metabolite concentrations during treatment of patients with chronic schizophrenia

Results presented in this article are focused on the variability in pharmac okinetics. The purpose of this study was (1) to investigate intra- and inte rindividual variabilities of pharmacokinetic parameters of clozapine and it s two main metabolites in plasma after multiple oral administration in 8 ch ronic schizophrenic patients (Study 1) and (2) to gain more information reg arding plasma concentrations of these drugs after multiple doses in a group of 25 treatment-responsive patients (Study 2). Patients were treated with clozapine in fixed daily doses (given every 8-12 hours) between 200 and 900 mg. Plasma drug concentrations were determined by highperformance liquid c hromatography. The mean volume of distribution and the total plasma clearan ce of clozapine, uncorrected for bioavailability, were 7 L/kg and 40.5 L/h, respectively. The terminal elimination half-lives averaged 10.5 hours for clozapine, 19.2 hours for norclozapine, and 8.6 hours for the N-oxide metab olite. Significant relationships were observed between clozapine and norclo zapine (or clozapine N-oxide) plasma concentrations. Large inter- and intra patient variations in pharmacokinetics were observed. Clozapine was general ly well tolerated by the patients, with sedation, hypersialorrhea, and tire dness as the most common side effects encountered. (C) 1999 the American Co llege of Clinical pharmacology.