Population pharmacokinetics, enzyme occupancy, and pharmacodynamic modeling of soticlestat in patients with developmental and epileptic encephalopathies

Autor: Wei Yin, Axel Facius, Mahnaz Asgharnejad, Gëzim Lahu, Majid Vakilynejad
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Clinical and Translational Science, Vol 17, Iss 3, Pp n/a-n/a (2024)
Druh dokumentu: article
ISSN: 1752-8062
1752-8054
DOI: 10.1111/cts.13722
Popis: Abstract Soticlestat (TAK‐935) is a first‐in‐class, selective inhibitor of cholesterol 24‐hydroxylase (CH24H) under phase III development for the treatment of the developmental and epileptic encephalopathies (DEEs), Dravet syndrome (DS), and Lennox–Gastaut syndrome (LGS). A previous model characterized the pharmacokinetics (PKs), CH24H enzyme occupancy (EO), and pharmacodynamics (PDs) of soticlestat in healthy volunteers. The present study extended this original model for patients with DEEs and investigated sources of variability. Model‐based simulations were carried out to optimize dosing strategies for use in clinical trials. Data from eight phase I and II trials of healthy volunteers or patients with DEEs receiving oral soticlestat 15–1350 mg were included, encompassing 218 individuals for population PK (PopPK) analyses and 306 individuals for PK/PD analyses. Dosing strategies were identified through model‐based simulations. The final mixed‐effect PopPK/EO/PD model consisted of a two‐compartment PK model and an effect‐site compartment in the PK/EO model; soticlestat concentrations at the effect site were linked to 24S‐hydroxycholesterol plasma concentrations using a semimechanistic inhibitory indirect response model. Covariates were included to account for sources of variability. Pediatric dosing strategies were developed for four body weight bands (10 to
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