Abstract Details

Title No Clinically Relevant Effects of Hepatic Impairment on the Pharmacokinetics of a Next Generation Prodrug Troriluzole

Topic General Neurology

Presentation(s) P4 - Poster Session 4 (11:45 AM-12:45 PM)

Poster/Presentation
Number 4-014

Objective Determine the effect of moderate hepatic impairment (HI) on the PK of riluzole after administration of troriluzole.

Background

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.

Design/Methods

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.

Results

Total riluzole AUC and C_max in subjects with moderate HI were within ~10% of those with normal hepatic function [AUC_0-inf: 814.29 (HI) vs 731.40 (HS); C_max: 112.31 (HI) vs 122.43 (HS)]. Unbound riluzole exposure was approximately 1.7-fold (AUC_0-inf) and 1.4-fold (C_max) 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.

Conclusions No clinically meaningful increases in riluzole exposure were observed in subjects with moderate hepatic impairment following troriluzole administration.

Authors/Disclosures
Heather Sevinsky (Biohaven) PRESENTER	Ms. Sevinsky has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Ms. Sevinsky has stock in Biohaven Pharmaceuticals.
Richard Bertz (Biohaven Pharmaceuticals)	Richard Bertz has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Richard Bertz has stock in Biohaven Pharmaceuticals.
Rachel Rozakis	No disclosure on file
Mary Donohue (Biohaven Pharmaceuticals, Inc.)	Mary Donohue has received personal compensation for serving as an employee of Biohaven Pharmaceuticals, Inc.. Mary Donohue has stock in Biohaven Pharmaceuticals, Inc..
Bharat Awsare (Biohaven)	Bharat Awsare has received personal compensation for serving as an employee of Biohaven. Bharat Awsare has or had stock in Biohaven.
Stephen Kaplita (Biohaven Pharmaceuticals)	No disclosure on file
Betty Hussey (Allucent)	No disclosure on file
Irfan Qureshi, MD (Biohaven Pharmaceuticals)	Dr. Qureshi has received personal compensation for serving as an employee of Biohaven. Dr. Qureshi has stock in Biohaven Pharmaceuticals.
Vladimir Coric	Vladimir Coric has received personal compensation for serving as an employee of Biohaven. Vladimir Coric has received personal compensation in the range of $1,000,000+ for serving as an officer or member of the Board of Directors for Bioahven. Vladimir Coric has stock in Biohaven. Vladimir Coric has received intellectual property interests from a discovery or technology relating to health care.

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