Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers

Clin Pharmacol Drug Dev. 2021 Jan;10(1):86-98. doi: 10.1002/cpdd.865.

PMID: 32851809

M Judith Peterschmitt, Nigel P S Crawford, Sebastiaan J M Gaemers

Highlights: Phase 1 studies were conducted in healthy volunteers to determine venglustat pharmacokinetics, pharmacodynamics, safety, and tolerability. Venglustat demonstrated a favorable safety and tolerability profile.

Abstract

Background: Venglustat is a small-molecule inhibitor of glucosylceramide synthase (GCS) that works to lower glucosylceramide (GL-1) production and, as a result, is anticipated to significantly lower the development of glucosylceramide-based glycosphingolipids. GCS inhibition has therapeutic potential for a wide range of disorders affecting glycosphingolipid metabolism because of its impact on glycosphingolipid synthesis. Venglustat is therefore being researched as a substrate reduction therapy for a variety of medical conditions, such as Gaucher disease type 3, Parkinson's disease linked to GBA mutations, Fabry disease, GM2 gangliosidosis, and autosomal dominant polycystic kidney disease. Venglustat's pharmacokinetics, pharmacodynamics, safety, and tolerability, as well as the impact of food on pharmacokinetics, were all determined during phase 1 investigations in healthy volunteers (single-dose and food-effect studies: NCT01674036; repeated-dose study: NCT01710826).

Results: Following a single oral dose of venglustat l-malate (2, 5, 15, 25, 50, 100, or 150 mg), venglustat demonstrated linear pharmacokinetics, rapid absorption (median tmax, 3.00-5.50 hours), systemic exposure unaffected by food, low apparent total body clearance (mean CL/F, 5.18-6.43 L/h), and pooled geometric mean t1/2z of 28.9 hours. With pooled accumulation ratios of 2.10 for Cmax and 2.22 for AUC0-24 and no statistically significant influence of dose or sex on accumulation, apparent steady state occurred after repeated once-daily oral doses of venglustat l-malate (5, 10, or 20 mg) for 14 days. The mean fraction of dose excreted unchanged in urine (fe0-24) was 26.3% to 33.1%. Time- and dose-dependent declines in plasma GL-1 and GM3 were observed.

Conclusion: Venglustat demonstrated a favorable safety and tolerability profile.

Keywords: xLSD, glucosylceramide (GL-1), glucosylceramide synthase (GCS) inhibition, substrate reduction therapy, venglustat