A Thorough QT/QTc Study of Clobazam in Healthy Volunteers.

PURPOSE

A thorough QT study was conducted to assess the proarrhythmic potential of clobazam and its active metabolite, N-desmethylclobazam (N-CLB).

METHODS

In this Phase I, single-site, randomized, double-blind, double-dummy, parallel-group study, healthy participants were randomized to 1 of 4 treatment groups: clobazam 40 mg/d (maximum therapeutic dosage), clobazam 160 mg/d (supratherapeutic dosage), placebo, or moxifloxacin 400 mg (active control).

FINDINGS

Of 280 enrolled participants (n = 70 per treatment arm), 250 (92%) completed the study; 194 were included in the pharmacokinetics population (clobazam 40 mg/d, n = 66; clobazam 160 mg/d, n = 62; and moxifloxacin, n = 66). Mean changes from baseline in QT interval placebo-corrected for heart rate using the Fridericia formula (primary end point), Bazett formula, and individual correction method (QTcF, QTcB, and QTcI, respectively) with clobazam 40 and 160 mg/d revealed no effect on QTc. No clinically relevant or treatment-related arrhythmias were observed, and there were no instances of second- or third-degree atrioventricular block. Given that clobazam is primarily demethylated to N-CLB by cytochrome P450 (CYP) enzyme, CYP3A4, the mean plasma time-concentration profile of clobazam was unchanged with the exclusion of CYP2C19 poor metabolizers. As N-CLB is metabolized by CYP2C19, the exclusion of CYP2C19 poor metabolizers resulted in slightly decreased mean plasma time-concentration profiles of N-CLB. Using a linear mixed-effects model, the effects of the clobazam and N-CLB C values on the placebo-corrected changes from baseline in QTcF, QTcI, and QTcB were near zero or slightly negative, and are not considered clinically important. The incidence of treatment-emergent adverse events was greatest in the clobazam groups (number of moderate AEs experienced by patients: PBO, 3/70; MOXI, 5/70; CLB 40 mg/d, 18/70; CLB 160 mg/d, 21/70; severe AEs: PBO, MOXI, & CLB 160 mg/d, 0; CLB 40 mg/d, 2/70); there were no serious AEs in any treatment group. A total of 10% of participants experienced benzodiazepine-withdrawal symptoms (16%, 23%, and 3% in the clobazam 40 and 160 mg/d groups and the moxifloxacin group, respectively).

IMPLICATIONS

The findings from this thorough QT study are consistent with existing clinical data and support the lack of proarrhythmic potential with clobazam.