Evaluation of Bioequivalence Between Clozapine Suspension and Tablet Formulations

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Clozapine is the most effective drug for schizophrenia. A suspension formulation of clozapine for patients who may have difficulty swallowing tablets was approved based on the 1996 US Food and Drug Administration (FDA) Guidance and has been launched in Australia, New Zealand and the UK. The objective of this study was to compare the bioequivalence of a new suspension formulation of clozapine with clozapine tablets (Clozaril(®)). The steady-state bioequivalence of a 50-mg/mL clozapine suspension and Clozaril(®) tablets was compared under fasting and fed conditions in a randomized, multiple-dose, two-way crossover study, consistent with the 2005 FDA Bioequivalence Guidance. Adult patients with schizophrenia established on once-daily doses of clozapine were administered Clozaril(®) tablets or clozapine suspension for 11 days, then switched to the other formulation for the next 11 days. On days 10 and 11 of each period, fasted (day 10) and fed (day 11) pharmacokinetic profiles were obtained over 24 h. Compared with the tablet formulation, point estimates for maximum plasma concentration (C(max)) and area under the plasma concentration-time curve during a dosage interval (τ) [AUCτ] for the suspension formulation were close to 100 %, and all 90 % confidence intervals (CIs) were between 80 % and 125 % under fasted (C(max) 99.91; 90 % CI 94.60, 104.70; AUC(τ) 99.55; 90 % CI 92.40, 100.70) and fed (C(max) 99.72; 90 % CI 93.70, 103.50; AUC(τ) 99.68; 90 % CI 93.40, 101.80) conditions. Food did not affect AUC(τ); however, C(max) was reduced by ~20 %, with a similar magnitude of change for both formulations. Safety/tolerability profiles were similar between the two formulations. The tablet and suspension formulations are bioequivalent, with similar safety profiles, under fed and fasted conditions.