Riluzole is a glutamate modulating agent approved for amyotrophic lateral sclerosis. Following oral riluzole, subjects with mild or moderate HI experience 1.7- to 3-fold higher AUC. Approximately 8% of riluzole-treated patients will experience elevations in alanine aminotransferase (ALT) levels >3X upper limit of normal (ULN).
Troriluzole is a novel, optimized, prodrug of riluzole, rationally designed to overcome significant first-pass metabolism, dose-dependent transaminase elevations, low oral bioavailability, high PK variability and the requirement of fasting around dosing. Due to its ability to bypass first pass metabolism, troriluzole may reduce riluzole burden on the liver.
BHV4157-104 was a Phase 1, single-dose, open-label study in 8 subjects with moderate HI (Child-Pugh score 7-9 points), and 8 healthy subjects (HS). All subjects received a single oral 100 mg dose of troriluzole (fasted). Subjects in the two groups were matched for age (± 10 years, but ≤80 years), body mass index (± 15%), and gender.
PK samples were collected pre-dose and through 144 hours (HI) and 72 hours (HS) post-dose. Riluzole PK parameters (total and unbound) were calculated by noncompartmental analysis.
Total riluzole AUC and Cmax in subjects with moderate HI were within ~10% of those with normal hepatic function [AUC0-inf: 814.29 (HI) vs 731.40 (HS); Cmax: 112.31 (HI) vs 122.43 (HS)]. Unbound riluzole exposure was approximately 1.7-fold (AUC0-inf) and 1.4-fold (Cmax) greater in subjects with moderate HI versus HS.
Troriluzole was well tolerated in both groups. There were no clinically meaningful trends in elevations of liver enzyme or values >3X ULN.