Abstract Details

Title Population Pharmacokinetic Modeling of Riluzole After Administration of a Next Generation Prodrug Troriluzole

Topic General Neurology

Presentation(s) S3 - General Neurology 1 (2:12 PM-2:24 PM)

Poster/Presentation
Number 007

Background Troriluzole is a novel prodrug rationally designed to improve the bioavailability, delivery and safety of the glutamate modulating agent riluzole (approved for amyotrophic lateral sclerosis).

Objective Characterize riluzole’s PK following troriluzole administration, evaluate the impact and clinical relevance of significant covariates on the PK variability and compare riluzole PK following troriluzole vs riluzole administration.

Design/Methods Riluzole quantifiable plasma concentrations were available for 169 healthy subjects (HS) from 8 Phase 1 studies and 810 patients from 5 Phase 2/3 studies receiving troriluzole, and 134 HS from 1 Phase 1 study receiving riluzole. Data analysis, popPK model evaluation, and postprocessing were conducted in NONMEM Version 7.4.4 and R Version 4.1.3.

Results

Riluzole PK was described by two-compartment model, with separate zero-order followed by first-order absorption for each drug, linked by relative bioavailability (F). The covariates included were sex, age, fluvoxamine use on apparent clearance CL/F, and food/evening dose on absorption rate constant (Ka).

In Phase 1 HS, troriluzole led to 53.8% higher F, 75.6% lower Ka, ~2.7-fold increase in duration of zero-order release, and ~50% lower interindividual variability in F and Ka overall, resulting in improved absorption and reduced PK variability vs riluzole. Food/or evening dose resulted in a ≤10% change in AUC despite 30.8% slower Ka. Concomitant fluvoxamine resulted in 55.6% decrease in CL/F. Sex and age were statistically significant, with modest decreases in CL/F (~22.3% for females and ~13.9% for 65 vs 45 years) not considered clinically relevant.

Conclusions Troriluzole administration resulted in improved riluzole PK including higher bioavailability, longer absorption duration, and lower PK variability vs riluzole administration. Food did not have a significant effect on bioavailability. Fluvoxamine use (strong CYP1A2 inhibitor) had a significant interaction. The results demonstrate distinct PK advantages of troriluzole and support once-daily dosing without regard to food.

Authors/Disclosures
Heather Sevinsky (Biohaven) PRESENTER	No disclosure on file
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.
Teodora Pene Dumitrescu (Allucent)	No disclosure on file
Yi Shuan Wu (Biogen, Inc.)	No disclosure on file
Angela Jeong	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.