Population pharmacokinetics, enzyme occupancy, and 24S-hydroxycholesterol modeling of soticlestat, a novel cholesterol 24-hydroxylase inhibitor, in healthy adults.

ABSTRACT: Soticlestat is a first-in-class, selective inhibitor of cholesterol 24-hydroxylase (CH24H), which catabolizes cholesterol to 24S-hydroxycholesterol (24HC) in the brain, in phase III development for Dravet syndrome and Lennox-Gastaut syndrome treatment. This study aimed to develop a model of soticlestat pharmacokinetics (PKs) and pharmacodynamics (PDs) using 24HC plasma concentrations and CH24H enzyme occupancy (EO) time profiles. Subsequently, model-based simulations were conducted to identify dosing strategies for phase II trials in children and adults with developmental and epileptic encephalopathies (DEEs). Four phase I trials of healthy adults involving oral administration of soticlestat 15-1350 mg were used to develop the mixed-effect population PK/EO/PD model. The population PK analy

SUBMITTER: Yin W 

PROVIDER: S-EPMC10339692 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature