Objective:

Assess, in a phase 1, open-label study, pharmacokinetics (PK), safety, and tolerability of single-dose (SD) and multiple-dose (MD) adjunctive carisbamate in patients ≥2 years old with Lennox-Gastaut syndrome (LGS).

Background:

Carisbamate, an investigational antiseizure medication (ASM), is in development for treatment of LGS-associated seizures in adult and pediatric patients.

Design/Methods:

Patients were enrolled into one of four cohorts: Cohort I (≥18 years), Cohort II (12 to <18 years), Cohort III (6 to <12 years), and Cohort IV (2 to <6 years). Cohorts I-III starting doses were 200, 140, and 60 mg/day, respectively. Cohort IV starting dose and regimen was to be determined from Cohort I-III results. SD phase (Days 1-3): carisbamate oral suspension administered on Day 1 followed by PK sampling for 48 hours. The MD phase (Days 3-87) employed twice-daily divided doses. After Day 17, maximum daily dose allowed was 600 mg/day pediatric equivalent. PK sampling occurred predose and for 12 hours postdose on Day 17. Trough PK sampling occurred on Days 45 and 73.

Results:

Eighteen patients enrolled (Cohort I, n=8; Cohort II, n=3; Cohort III, n=7; ages 6-52 years); 16 completed the entire study. Cohort IV was withdrawn due to low enrollment. Following SD, carisbamate plasma concentrations reached T_max at 1-2 hours postdose in all three cohorts; increases to mean C_max, AUC_0-last, and AUC_0-inf were linear and dose-proportional. MD steady-state PK parameters on Day 17  increased in a linear and dose-proportional manner. The most frequently reported treatment-emergent adverse events (TEAEs) were nervous system‒related; most were mild (n=6, 33.3%) or moderate (n=5, 27.8%).

Conclusions:

Carisbamate exhibited linear, dose-proportional PK after SD and MD in pediatric and adult patients with LGS and was generally safe and well-tolerated. PopulationPK modeling showed that adult dosing regimens were appropriate for patients ≥12 years of age whereas dosing for patients ages 4 to <12 should be weight-based.