Authors :
Presenting Author: Ihab Abdallah, PhD – SK Life Science, Inc.
Vijay Vashi, PhD – SK Life Science, Inc.
Gopal Krishna, PhD – SK Life Science, Inc.
Fredrik Jonsson, PhD – qPharmetra LLC
Sunita N Misra, MD – SK Life Science, Inc.
Rationale:
Cenobamate is an antiseizure medication approved in the United States (XCOPRI®) for the treatment of focal seizures in adults. Limited retrospective evidence suggests similar efficacy in children, but further studies are needed to assess cenobamate dosing for safety, tolerability, and efficacy in children. Two open-label clinical studies (Study C039 [NCT04903314] and Study C040 [NCT05067634]) assessed the pharmacokinetics (PK), safety, and tolerability of cenobamate following single and multiple dosing in pediatric patients (2 to < 18 years old) with focal seizures. We report here on the evaluation of dosing regimens in the adolescent subgroup of patients 12 to < 18 years old. Methods:
Pediatric and adolescent PK data from studies C039 and C040, as well as data from healthy adults in bioavailability study C037, were incorporated into a population PK (PopPK) model of previous studies of adult patients with focal seizures to determine the appropriate cenobamate dosing regimen (ie, body weight-based or flat-fixed) in adolescent patients. For adolescent subgroup simulations, age and body weight from 2,000 virtual patients were randomly sampled from the CDC database. Dosing regimens were simulated assuming a 10-week up-titration period and maintenance dosing of 10 weeks. Adult exposures at 200-mg/day flat dosing were simulated using resampled body weight/age from adult patients in the database. Simulations were run for both body weight-based and flat-fixed daily dosing. Steady-state exposures (area under the curve [AUC] at steady-state) were simulated at the end of each target dose level in the 2-8 mg/kg (ie, 100-400 mg, adult equivalent) once-daily (QD) range.Results:
PK data were available for 48 patients in the adolescent subgroup of C039/40, 77 adult and pediatric patients from studies C037/39/40, and 960 adult patients from previously completed studies. Cenobamate PK was adequately described by a two-compartment model with first-order absorption and first-order elimination. The PopPK model indicated that the mean (90% prediction interval or PI) AUCs at steady state in adolescents on a cenobamate weight-based dose of 4 mg/kg QD (510 [251, 883] µg•h/mL) or flat dose of 200 mg QD (546 [260, 963] µg•h/mL) were comparable to the mean (90% PI) AUC at steady state in adults on a flat (ie, modal) dose of 200 mg QD (434 [207, 777] µg•h/mL). Exposures at all respective target doses (ie, mg/kg body weight-based or mg flat-fixed in adolescents vs flat-fixed in adults) were comparable. Conclusions:
Cenobamate exposures in adolescent patients from the flat (mg) QD target doses of 100-400 mg were similar to those in adult subjects at the same respective approved cenobamate adult doses.
Funding:
Funded by SK Life Science, Inc.