Population Pharmacokinetic Modeling of Riluzole After Administration of a Next Generation Prodrug Troriluzole
Richard Bertz1, Teodora Pene Dumitrescu2, Yi Shuan Wu2, Angela Jeong2, Heather Sevinsky1, Irfan Qureshi1, Vladimir Coric1
1Biohaven Pharmaceuticals, Inc, 2Allucent
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.
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).
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.