Preclinical characterization of pharmacokinetics, enzyme occupancy, and pharmacodynamics of soticlestat (TAK-935), a novel cholesterol 24-hydroxylase inhibitor.

The conversion of cholesterol to 24S-hydroxycholesterol (24HC) is a brain-specific reaction catalyzed by cholesterol 24-hydroxylase (CH24H). Soticlestat, a specific inhibitor of CH24H, has the potential to reduce 24HC levels in the brain; 24HC is a neuroactive oxysterol that modulates several receptors and ion channels involved in regulating neural excitability. Soticlestat has been investigated as an additional treatment option for seizures associated with Dravet and Lennox-Gastaut syndromes. Comprehensive preclinical evaluation of pharmacokinetics (PK), target enzyme occupancy (EO), and pharmacodynamics (PDs)-including confirmation of their interrelationships within the brain as the target tissue-is essential for elucidating the mechanism of action of soticlestat. Preclinical data on PK, EO, and PD in rodent models facilitate translational modeling, thereby informing rational human dose selection. A divergence in the temporal profiles of soticlestat concentrations between brain and plasma was observed, with prolonged brain exposure relative to plasma clearance, consistent with the compound's slow dissociation from CH24H. Herein, we characterized the PK, PD, and EO profiles of soticlestat in rodents and demonstrated the relationship between CH24H inhibition and 24HC reduction. Soticlestat demonstrated a delayed-effect model in mice, with time lags between PK and PD as well as between brain and plasma pharmacokinetics. Subsequently, the steady-state PK/PD analysis after subcutaneous infusion in CH24H wild-type [CH24H(+/+)] and knockout [CH24H(-/-)] mice provided comprehensive insights into the model linking the PK, EO, and PD profiles of soticlestat. SIGNIFICANCE STATEMENT: In the present study, a clear relationship between the pharmacokinetics, target enzyme occupancy, and pharmacodynamic markers of cholesterol 24-hydroxylase for soticlestat in rodents. The preclinical pharmacokinetic/enzyme occupancy/pharmacodynamic data for soticlestat provide comprehensive mechanistic and quantitative insights into clinical population models. Importantly, these data emphasize the potential of enzyme occupancy and pharmacodynamics as strategic tools for facilitating translational research in central nervous system drug development.