Rationale: Carisbamate, an investigational antiseizure medication (ASM) effective at some doses for focal seizures in adult patients, is in development for the treatment of Lennox-Gastaut syndrome (LGS)-associated seizures in adult and pediatric patients.
This phase 1, open-label study assessed the pharmacokinetics (PK), safety, and tolerability of single and multiple doses of carisbamate in patients ≥2 years old with LGS. Results were incorporated into a population PK (PopPK) analysis to determine dosing for patients 4 to 17 years old, who were to be enrolled in a double-blind, placebo-controlled study of carisbamate in LGS (NCT05219617).
Methods: Male or female LGS patients ≥2 years old receiving 1 to 3 concomitant ASMs were to be enrolled in 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). The study included a 28-day baseline and 87-day treatment period. Starting doses (determined from adult studies and juvenile rodent toxicity studies) were 200, 140, and 60 mg/day for Cohorts I-III, respectively.
The Cohort IV starting dose and regimen was to be determined from Cohort I-III results. Patients received a single dose of carisbamate oral suspension on Day 1 followed by PK sampling for 48 hours. From Day 3 on, the starting dose was administered in two divided doses. On Day 17, PK sampling occurred pre-dose and for 12 hours post-dose. After Day 17, carisbamate dose could be increased every 7-14 days to a maximum pediatric equivalent of 600 mg/day. Trough PK samples were collected on Days 45 and 73. PK parameters assessed included C
max, T
max, AUC
0-last, and AUC
0-inf (single doses) and AUC at steady state (AUC
0-tau) and C
max (multiple doses).
Results: All 18 patients enrolled (Cohort I, n=8; Cohort II, n=3; Cohort III, n=7; ages 6-52 years) were included in the PK and safety analysis; 16 completed the entire study. Cohort IV was withdrawn due to low enrollment (related to the COVID pandemic). Following single doses, carisbamate plasma concentrations reached T
max 1-2 hours post-dose in all 3 cohorts, and mean C
max, AUC
0-last, and AUC
0-inf increased in a linear and dose-proportional manner. Multiple-dose steady-state PK parameters on Day 17 also increased in a linear and dose proportional manner. When possible, results were confirmed by dose normalization analyses. The most frequently reported treatment-emergent adverse events (TEAEs) were nervous system‒related. Most TEAEs were mild (n=6, 33.3%) or moderate (n=5, 27.8%); 1 severe TEAE (affective disorder possibly related to study drug) occurred. No serious TEAEs occurred. Two patients discontinued the study, 1 due to moderate sedation and 1 due to physician decision.
Conclusions: Carisbamate exhibited linear, dose-proportional PK after single and multiple dosing in pediatric and adult patients with LGS. Treatment with carisbamate was generally safe and well-tolerated, with nervous system adverse events most common. PopPK 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.
Funding: Funded by SK Life Science, Inc.