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

Autor: Theresa T. Pham, Allena J. Ji, Jyoti Sharma, Sebastiaan J.M. Gaemers, M. Judith Peterschmitt, Nigel P. S. Crawford
Rok vydání: 2020
Předmět:
Adult
Male
monosialodihexosylganglioside (GM3)
Quinuclidines
Adolescent
Cmax
Autosomal dominant polycystic kidney disease
Administration
Oral
Pharmaceutical Science
Original Manuscript
Gangliosidosis
Pharmacology
glucosylceramide synthase (GCS) inhibition
Glucosylceramides
030226 pharmacology & pharmacy
Young Adult
03 medical and health sciences
0302 clinical medicine
Double-Blind Method
Pharmacokinetics
Gangliosides
medicine
Humans
Pharmacology (medical)
Substrate reduction therapy
Enzyme Inhibitors
glucosylsphingosine (lyso‐GL‐1)
Cross-Over Studies
globotriaosylceramide (GL‐3)
business.industry
Articles
Middle Aged
venglustat (GZ/SAR402671
Genz‐682452)
medicine.disease
Fabry disease
Healthy Volunteers
substrate reduction therapy
Tolerability
Glucosyltransferases
030220 oncology & carcinogenesis
Pharmacodynamics
Female
glucosylceramide (GL‐1)
Carbamates
business
Zdroj: Clinical Pharmacology in Drug Development
ISSN: 2160-7648
2160-763X
Popis: Venglustat is a small‐molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL‐1) and thus is expected to substantially reduce formation of glucosylceramide‐based glycosphingolipids. Because of its effect on glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism. Therefore, venglustat is under development for substrate reduction therapy in multiple diseases, including Gaucher disease type 3, Parkinson's disease associated with GBA mutations, Fabry disease, GM2 gangliosidosis, and autosomal dominant polycystic kidney disease. Phase 1 studies were conducted in healthy volunteers to determine venglustat pharmacokinetics, pharmacodynamics, safety, and tolerability and to assess food effects on pharmacokinetics (single‐dose and food‐effect studies: NCT01674036; repeated‐dose study: NCT01710826). 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. Following repeated once‐daily oral doses of venglustat l‐malate (5, 10, or 20 mg) for 14 days, apparent steady state occurred within 5 days of repeated dosing, with pooled accumulation ratios of 2.10 for Cmax and 2.22 for AUC0–24, and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe0–24) was 26.3% to 33.1%. Plasma GL‐1 and GM3 decreased time‐ and dose‐dependently. Venglustat demonstrated a favorable safety and tolerability profile.
Databáze: OpenAIRE
Externí odkaz: