Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers
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 inhibit...
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| Published in | Clinical pharmacology in drug development Vol. 10; no. 1; pp. 86 - 98 |
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| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
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United States
Wiley Subscription Services, Inc
01.01.2021
John Wiley and Sons Inc |
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| Abstract | 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. |
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| AbstractList | 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. 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 t , 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 t 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 C and 2.22 for AUC , and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe ) was 26.3% to 33.1%. Plasma GL-1 and GM3 decreased time- and dose-dependently. Venglustat demonstrated a favorable safety and tolerability profile. 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 t max , 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 t 1/2z 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 C max and 2.22 for AUC 0–24 , and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe 0–24 ) was 26.3% to 33.1%. Plasma GL‐1 and GM3 decreased time‐ and dose‐dependently. Venglustat demonstrated a favorable safety and tolerability profile. 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. 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.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. |
| Author | Pham, Theresa T. Peterschmitt, M. Judith Crawford, Nigel P. S. Gaemers, Sebastiaan J. M. Ji, Allena J. Sharma, Jyoti |
| AuthorAffiliation | 2 Sanofi Bridgewater New Jersey USA 1 Sanofi Genzyme Cambridge Massachusetts USA 5 PPD Development, LLC Austin Texas USA 4 Sanofi Genzyme Framingham Massachusetts USA 3 Sanofi Genzyme Amsterdam The Netherlands |
| AuthorAffiliation_xml | – name: 2 Sanofi Bridgewater New Jersey USA – name: 5 PPD Development, LLC Austin Texas USA – name: 1 Sanofi Genzyme Cambridge Massachusetts USA – name: 4 Sanofi Genzyme Framingham Massachusetts USA – name: 3 Sanofi Genzyme Amsterdam The Netherlands |
| Author_xml | – sequence: 1 givenname: M. Judith surname: Peterschmitt fullname: Peterschmitt, M. Judith email: Judith.Peterschmitt@sanofi.com organization: Sanofi Genzyme – sequence: 2 givenname: Nigel P. S. surname: Crawford fullname: Crawford, Nigel P. S. organization: Sanofi – sequence: 3 givenname: Sebastiaan J. M. surname: Gaemers fullname: Gaemers, Sebastiaan J. M. organization: Sanofi Genzyme – sequence: 4 givenname: Allena J. surname: Ji fullname: Ji, Allena J. organization: Sanofi Genzyme – sequence: 5 givenname: Jyoti surname: Sharma fullname: Sharma, Jyoti organization: Sanofi – sequence: 6 givenname: Theresa T. surname: Pham fullname: Pham, Theresa T. organization: PPD Development, LLC |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32851809$$D View this record in MEDLINE/PubMed |
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| Keywords | glucosylceramide (GL-1) glucosylceramide synthase (GCS) inhibition venglustat (GZ/SAR402671; Genz-682452) substrate reduction therapy globotriaosylceramide (GL-3) glucosylsphingosine (lyso-GL-1) monosialodihexosylganglioside (GM3) |
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| Snippet | Venglustat is a small‐molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL‐1) and thus is expected to... Venglustat is a small-molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL-1) and thus is expected to... |
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| SubjectTerms | Administration, Oral Adolescent Adult Carbamates - administration & dosage Carbamates - adverse effects Carbamates - pharmacokinetics Cross-Over Studies Disease Double-Blind Method Enzyme Inhibitors - adverse effects Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Female Gangliosides - blood globotriaosylceramide (GL‐3) glucosylceramide (GL‐1) glucosylceramide synthase (GCS) inhibition Glucosylceramides - blood glucosylsphingosine (lyso‐GL‐1) Glucosyltransferases - antagonists & inhibitors Healthy Volunteers Humans Kidney diseases Male Middle Aged monosialodihexosylganglioside (GM3) Original Manuscript Pharmacodynamics Pharmacokinetics Quinuclidines - administration & dosage Quinuclidines - adverse effects Quinuclidines - pharmacokinetics substrate reduction therapy venglustat (GZ/SAR402671; Genz‐682452) Young Adult |
| Title | Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers |
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