Model-Based Analysis of Pharmacokinetics of Venglustat, a small-molecule inhibitor of glucosylceramide synthase, Using Pooled Data from Healthy Subjects and Patients with Lysosomal Storage Disorders
Authors: SHAO SHUAI , Shao Shuai , Gao Yue , Cartot-Cotton Sylvaine , Sharma Jyoti , Xu Christine , Macha Sreeraj , Ahamadi Malidi 
Published: February 2025

Objective: Venglustat is a small-molecule inhibitor of glucosylceramide synthase (GCS), which reduces the synthesis of glucosylceramide (GL-1), a key precursor for complex glycosphingolipids [1]. This inhibition is anticipated to have significant therapeutic potential in a variety of disorders, including lysosomal storage diseases and other conditions linked to elevated levels of GL-1 or related glycosphingolipids. Using a model-based approach, we characterized the pharmacokinetic (PK) properties of Venglustat in healthy subjects and patients and quantified the effect of intrinsic and extrinsic factors on exposure. Methods: A total of 4325 serum concentrations from 68 healthy subjects and 476 adult patients associated Parkinson's disease (GBA-PD), Fabry, Gaucher disease type 3 (GD3), Autosomal dominant polycystic kidney disease (ADPKD) and Monosialic ganglioside gangliosidosis (GM2) diseaseswere used to describe the PK of Venglustat. The relationships between PK parameters and various baseline covariates (e.g., age, gender, race, laboratory parameters of liver and renal function, and type of disease) were examined. The final model was validated using visual predictive check (VPC) and bootstrap. Simulations were performed to detect clinically relevant effects of selected covariates. Results: A two-compartment population PK model with linear clearance from the central compartment described Venglustat concentration. Disease type was included in the final base model to account for the variability of the magnitudes of exposures across diseases type considered in the analysis dataset (Fabry and GM2). eGFR was identified as a covariate for clearance, while age and gender were identified as covariates for the central volume of distribution. With a 20% increase in eGFR (ml/min), clearance is predicted to increase by 9.6%. With a 20% increase in age, central volume of distribution is predicted to increase by 10.2%. Females had an estimated 23% reduction in central volume. These marginal effects on exposure were clinically insignificant on pharmacokinetic properties of Venglustat. Other tested covariates including body weight, race, alkaline phosphatase (ALP), creatinine clearance, albumin, alanine amino transferase, aspartate amino transferase and bilirubin did not have an impact on exposure. Conclusion: The PK of venglustat was adequately described by a two-compartment model with first order absorption and linear elimination. PK properties of venglustat in healthy subjects were comparable to those of GBA-PD, GD3 and ADPKD patients. Fabry and GM2 disease exerted a notable effect explaining the between-subject variability venglustat PK. There was no clinically meaningful effect of intrinsic or extrinsic factor on Venglustat exposure. Disclosures: Shao S, Gao Y, Cartot-Cotton S, Sharma J, Xu C, Macha S, Ahamadi M: Sanofi - employees. may hold stock and/or stock options in the company of Sanofi.Citations: [1] Peterschmitt, M. Judith, et al. "Pharmacokinetics, pharmacodynamics, safety, and tolerability of oral venglustat in healthy volunteers." Clinical Pharmacology in Drug Development 10.1 (2021): 86-98.