Carisbamate treatment of adult and pediatric patients with Lennox-Gastaut syndrome: A phase 1 pharmacokinetic, safety, and tolerability study.

OBJECTIVE

To characterize the single- and multiple-dose pharmacokinetics, safety, and tolerability of carisbamate oral suspension in adult and pediatric patients with Lennox-Gastaut syndrome (LGS).

METHODS

This phase 1, open-label study (NCT03731715) enrolled patients into four age cohorts: Cohort I (C-I), ≥ 18 years; Cohort II (C-II), 12 to < 18 years; Cohort III (C-III), 6 to < 12 years; Cohort IV (C-IV), 2 to < 6 years (C-IV withdrawn due to inability to enroll patients). On Day 1, patients received a single dose of carisbamate: 200 mg (C-I), 140 mg (C-II), 60 mg (C-III), followed by twice-daily multiple-dosing Days 3-17: 100 mg (C-I), 70 mg (C-II), 30 mg (C-III). Pharmacokinetic parameters were determined using noncompartmental analysis. Safety was also assessed.

RESULTS

Eighteen patients (C-I: n = 8; C-II: n = 3; C-III: n = 7) were included; 16 (89%) completed the study. Following single doses, carisbamate was rapidly absorbed (tmax, 1-2 h post-dose), with a mean t1/2 of ∼12 h in C-I and C-II and ∼8 h in C-III. After single- and multiple-doses, mean Cmax, AUC0-last, and AUC0-inf increased dose-proportionally. Total carisbamate exposures were comparable across cohorts after dose normalization. Mean (SD) accumulation ratios following multiple dosing were 1.66 (0.15; C-I) and 1.69 (0.06; C-II). Treatment-emergent adverse events (TEAEs) occurred in 66.7% of patients, most commonly nervous system TEAEs (22.2%). One severe TEAE (affective disorder) occurred, and one patient discontinued due to an AE (sedation). No serious TEAEs or deaths occurred.

CONCLUSIONS

In this small phase 1 PK/safety study, carisbamate appeared to exhibit linear, dose-proportional pharmacokinetic parameters in pediatric and adult LGS patients at doses of 60-200 mg/day and was generally well tolerated during short-term treatment.