Background and objective: Food has reportedly not affected the systemic bioavailability of the atypical antipsychotic drug clozapine. However, searches of the medical literature could find no studies to support this food claim for any formulation of clozapine. The purpose of the current study was to assess the effect of food on the bioavailability and pharmacokinetics of clozapine orally disintegrating tablet (ODT) following single 12.5 mg doses in the healthy subjects in fasted and fed conditions.

Methods: This was a randomized, open-label, two-way crossover study in which healthy males aged 18–45 years completed two dosing periods. In period I, subjects received one dose of clozapine ODT 12.5mg after an overnight fast and in period II they received one dose of clozapine ODT 12.5 mg within 30 minutes of consuming a high-fat/-calorie breakfast. Venous blood samples were taken at regular intervals before and after study drug administration, and plasma concentrations of clozapine and desmethylclozapine were measured from each blood sample. Standard pharmacokinetic parameters were calculated. Safety and tolerability were also assessed.

Results: Twenty-four subjects were enrolled: all the subjects completed the study and were included in the pharmacokinetic analyses. Pharmacokinetic results demonstrated significant differences in mean plasma concentration-time curves between fasted and fed conditions for both clozapine and desmethylclozapine at various time points after administration of a single clozapine ODT 12.5mg dose. For both clozapine and desmethylclozapine, the lower limits of the 90% confidence intervals (CIs) for the geometric mean fed-to-fasted maximum plasma concentration (C_max) ratios (0.73 for both clozapine and desmethylclozapine) were below the bioequivalence lower limit, 0.80. The mean C_max of both clozapine and desmethylclozapine was decreased by ∼20% when clozapine ODT was administered after a high-fat/-calorie breakfast. However, the 90% CIs for the fed-to-fasted ratios of geometric means of area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC_last) [1.01, 1.15 for clozapine; 1.00, 1.18 for desmethylclozapine) and from time zero to infinity (AUC∞) [1.03, 1.14 for clozapine; 1.01, 1.15 for desmethylclozapine] were within the bioequivalence boundaries of 0.80–1.25. There were no serious adverse events, discontinuations due to adverse events, or abnormalities in clinical laboratory evaluations. Seventy-one adverse events were reported and 96% were mild in intensity — the most common adverse event was somnolence (42/71 events). Two severe adverse events (syncope, n=1 fasted subject; vasovagal syncope, n=1 fed subject) were reported ∼4 hours after administration of clozapine ODT and asystole (5–10 seconds) was associated with syncope in the fasted subject.

Conclusions: When compared with drug administration in the fasted state, coadministration of food was shown to decrease the rate of clozapine absorption from clozapine ODT 12.5mg as assessed by C_max but had no effect on the extent of clozapine absorption as assessed by AUC_last and AUC_∞. The C_max value for clozapine was ∼20% lower in the fed versus the fasted state. Thus, clozapine ODT should be administered at least 1 hour before meals or after a light meal. The reported adverse events in 24 healthy male subjects were consistent with those expected from healthy subjects taking oral clozapine.

This study was funded by Azur Pharma, Ltd, Dublin, Ireland. The authors declare that this manuscript is an accurate representation of the study results. The authors disclose that Dr DiSanto is a pharmaceutical scientific consultant for Azur Pharma, Ltd, and Dr Golden is an employee of Azur Pharma, Inc. and holds stock in the company. Both authors are fully responsible for the methodology, inclusion and interpretation of data, and for the conclusions expressed in this article. The authors had full access to the data, reviewed each manuscript draft, and approved the final manuscript. We would like to thank Joe Riley for his editorial support during preparation of the manuscript. We would also like to thank Mira Hong, PhD, and Ping Guo, PhD, from Frontage Laboratories, Inc. for the quantitative analyses of clozapine and desmethylclozapine and Biostudy Solutions LLC for the statistical analyses.

Authors and Affiliations

1. ARD Pharmaceutical Consulting, Gobles, Michigan, USA

   Anthony R. DiSanto

2. Medical Affairs, Azur Pharma, Inc., 1818, Market Street, Suite 2350, Philadelphia, Pennsylvania, PA 19103, USA

   Gil Golden (Vice President)

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