Effect of caffeine on clozapine pharmacokinetics in healthy volunteers

Aims To assess the effects of caffeine on the pharmacokinetics of clozapine in healthy volunteers. Methods This was an open label randomized crossover study in 12 nonsmoking healthy male volunteers. The subjects received a single oral dose of 12.5 mg clozapine in each phase with or without concomitant intake of caffeine (mean dose: 550 mg day−1, range: 400–1000 mg day−1 ). Serum concentrations of clozapine and its metabolites desmethyl-clozapine and clozapine-N-oxide were measured during a 48 h period in each phase. In addition, serum concentrations of caffeine and the metabolite paraxanthine were monitored. Results A 19% increase in mean clozapine AUC(0,∞) (P=0.05) and a 14% decrease of mean oral clearance of clozapine were observed during concomitant intake of caffeine (P=0.05) compared with intake of only clozapine. Statistically significant decreases of mean ratios between AUC(0,12h) for desmethyl-clozapine and AUC(0,12h) for clozapine (−18%), and between AUC(0,12h) for clozapine-N-oxide and AUC(0,12h) for clozapine (−23%) were observed during the caffeine phase (P=0.03 and 0.02, respectively). Oral clearance of clozapine and the ratio AUC(0,12h) for desmethyl-clozapine/AUC(0,12h) for clozapine were correlated with the paraxanthine/caffeine ratio in serum after intake of caffeine (rs=0.62; P=0.03 and rs=0.77; P=0.003, respectively). Conclusions These results suggest that caffeine in daily doses of 400–1000 mg inhibits the metabolism of clozapine to an extent that might be clinically significant in certain individuals.