{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:19:20Z","timestamp":1790518760204,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T00:00:00Z","timestamp":1598400000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Venglustat is a small\u2010molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL\u20101) and thus is expected to substantially reduce formation of glucosylceramide\u2010based 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\n                    <jats:italic>GBA<\/jats:italic>\n                    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\u2010dose and food\u2010effect studies: NCT01674036; repeated\u2010dose study: NCT01710826). Following a single oral dose of venglustat\n                    <jats:sc>l\u2010<\/jats:sc>\n                    malate (2, 5, 15, 25, 50, 100, or 150\u00a0mg), venglustat demonstrated linear pharmacokinetics, rapid absorption (median t\n                    <jats:sub>max<\/jats:sub>\n                    , 3.00\u20135.50\u00a0hours), systemic exposure unaffected by food, low apparent total body clearance (mean CL\/F, 5.18\u20136.43\u00a0L\/h), and pooled geometric mean t\n                    <jats:sub>1\/2z<\/jats:sub>\n                    of 28.9\u00a0hours. Following repeated once\u2010daily oral doses of venglustat\n                    <jats:sc>l\u2010<\/jats:sc>\n                    malate (5, 10, or 20\u00a0mg) for 14\u00a0days, apparent steady state occurred within 5\u00a0days of repeated dosing, with pooled accumulation ratios of 2.10 for C\n                    <jats:sub>max<\/jats:sub>\n                    and 2.22 for AUC\n                    <jats:sub>0\u201324<\/jats:sub>\n                    , and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe\n                    <jats:sub>0\u201324<\/jats:sub>\n                    ) was 26.3% to 33.1%. Plasma GL\u20101 and GM3 decreased time\u2010 and dose\u2010dependently. Venglustat demonstrated a favorable safety and tolerability profile.\n                  <\/jats:p>","DOI":"10.1002\/cpdd.865","type":"journal-article","created":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T13:56:48Z","timestamp":1599055008000},"page":"86-98","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers"],"prefix":"10.1002","volume":"10","author":[{"given":"M. Judith","family":"Peterschmitt","sequence":"first","affiliation":[{"name":"Sanofi Genzyme Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel P. S.","family":"Crawford","sequence":"additional","affiliation":[{"name":"Sanofi Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan J. M.","family":"Gaemers","sequence":"additional","affiliation":[{"name":"Sanofi Genzyme Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allena J.","family":"Ji","sequence":"additional","affiliation":[{"name":"Sanofi Genzyme Framingham Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyoti","family":"Sharma","sequence":"additional","affiliation":[{"name":"Sanofi Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa T.","family":"Pham","sequence":"additional","affiliation":[{"name":"PPD Development, LLC Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2018.01.007"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.107"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2006.05.027"},{"issue":"1","key":"e_1_2_10_5_1","first-page":"72","article-title":"Gaucher disease: the metabolic defect, pathophysiology, phenotypes and natural history","volume":"12","author":"Baris HN","year":"2014","journal-title":"Pediatr Endocrinol Rev"},{"key":"e_1_2_10_6_1","volume-title":"StatPearls","author":"Bokhari SRA","year":"2020"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/1566523218666180404162622"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14393"},{"issue":"6","key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1016\/S0022-2275(20)39163-X","article-title":"Role of lactosylceramide and MAP kinase in the proliferation of proximal tubular cells in human polycystic kidney disease","volume":"37","author":"Chatterjee S","year":"1996","journal-title":"J Lipid Res"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)41159-9"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds172"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2171"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/diseases4040033"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18020441"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-03-273151"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616152114"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2016.53"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2015.00088"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2018.12.336"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.01.018"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2018.12.298"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12425"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1080\/03602532.2016.1239630"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.4155\/bio.15.77"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2004.038323"},{"issue":"15","key":"e_1_2_10_26_1","doi-asserted-by":"crossref","first-page":"S4.002","DOI":"10.1212\/WNL.92.15_supplement.S4.002","article-title":"Safety, tolerability and pharmacokinetics of oral venglustat in Parkinson's disease patients with a GBA mutation (S4.002)","volume":"92","author":"Fischer T","year":"2019","journal-title":"Neurology"}],"container-title":["Clinical Pharmacology in Drug Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpdd.865","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpdd.865","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpdd.865","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T22:40:45Z","timestamp":1723502445000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/cpdd.865"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,26]]},"references-count":25,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1]]}},"alternative-id":["10.1002\/cpdd.865"],"URL":"https:\/\/doi.org\/10.1002\/cpdd.865","archive":["Portico"],"relation":{},"ISSN":["2160-763X","2160-7648"],"issn-type":[{"value":"2160-763X","type":"print"},{"value":"2160-7648","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,26]]},"assertion":[{"value":"2020-01-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-08-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}