Soticlestat at a dose of 100 to 300  mg twice a day is optimal for testing in phase 2 clinical trials in adults with epileptic encephalopathies, including Lennox-Gastaut syndrome (LGS), according to model-based simulations. For children, the dosing strategy to be tested should be adjusted according to weight.

These findings were published in the journal Clinical and Translational Science and “illustrate the utility of model-based simulations to select dosing strategies for clinical trials,” according to the authors. 

Read more about experimental therapies for LGS

To develop a pharmacokinetic and pharmacodynamic model of soticlestat, the researchers led by Majid Vakilynejad, PhD, from Takeda Pharmaceuticals in Cambridge, Massachusetts, conducted model-based simulations with the ultimate aim of identifying dosing strategies for phase 2 clinical trials. 

The team used the concentrations of 24S-hydroxycholesterol in the plasma and the time profiles of cholesterol 24-hydroxylase (CH24H) enzyme occupancy to develop their model.

They collected data from 4 phase 1 clinical trials in healthy adults in which 15 to 1350  mg of soticlestat were administered. 

For the pharmacokinetic analysis, they used 1727 observations from 104 people, while for the pharmacokinetic, enzyme occupancy analysis, they used 20 observations from 11 people. Finally, for the pharmacokinetic/pharmacodynamic analysis, they used 2270 observations from 99 people.

They then used simulations based on the pharmacokinetic, enzyme occupancy, and pharmacodynamic observations to identify optimal dosing strategies. 

“The model described the observed data well and comprised a 2-compartment model with dose as a covariate on peripheral volume, linear elimination, and intercompartmental clearance,” the researchers wrote. “Transit and effect-site compartments were included to accommodate different dosage forms and the delay between plasma drug concentrations and [enzyme occupancy].”

Soticlestat is a selective CH24H inhibitor that is currently being tested in phase 3 clinical trials for the treatment of LGS and Dravet syndrome.


Yin W, Facius A, Wagner T, et al. Population pharmacokinetics, enzyme occupancy, and 24S-hydroxycholesterol modeling of soticlestat, a novel cholesterol 24-hydroxylase inhibitor, in healthy adults. Clin Transl Sci. Published online May 22, 2023. doi:10.1111/cts.13517