Abstracts

Rationale: Clobazam 5-, 10-, and 20-mg tablets are available as adjunctive therapy for adult and pediatric patients with Lennox-Gastaut syndrome (LGS). For LGS patients who have difficulty swallowing tablets, Lundbeck LLC has developed an oral suspension formulation of clobazam. As a suspension formulation is a new dosage form, we conducted a single-dose bioavailability study vs. the commercial tablet formulation. Methods: This Phase I study was a randomized, open-label, two-way crossover study investigating the relative bioavailability, safety and tolerability of oral suspension vs. oral tablets following a single 20-mg dose to healthy male and female study participants (N=30). Doses were administered on Days 1 and 15. Each administration was separated by a washout period of 14 days. The pharmacokinetic profiles of clobazam and N-desmethylclobazam (N-CLB) were obtained from serial plasma concentrations during 312 hours post-doses. The relative bioavailability of suspension compared with that of a clobazam tablet was evaluated using bioequivalence criteria: the 90% confidence intervals (CIs) of the ratios of the oral suspension to the oral tablet for the pharmacokinetic parameters of AUC_0-inf and C_max for clobazam were contained within the interval from 0.80 to 1.25. Results: The suspension/tablet ratio point estimate and 90% CIs for CLB were: C_max = 1.19 (1.12 to 1.27); AUC_0-last = 0.997 (0.977 to 1.02); and AUC_0-inf = 0.995 (0.976 to 1.01). Thus, bioequivalence criteria were met for AUC_0-last and AUC_0-inf. However, for C_max, the upper boundary of the 90% CI was just outside the bioequivalence limit of 1.25. All other parameters of exposure were similar. The slight increase observed in C_max was a consequence of the physicochemical properties of the suspension dosage form (i.e., a suspension is designed to deliver the drug faster than a tablet) and were not considered clinically meaningful, as two dissimilar dosage forms were compared. Conclusions: The 20-mg clobazam oral suspension was functionally bioequivalent to 20-mg commercial tablets. Clobazam has a wide therapeutic window and is intended for long-term administration for patients with chronic LGS. Thus, the slight increase in C_max is clinically insignificant. There were no clinically relevant differences in safety and tolerability between the two formulations.