Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial
Abstract Background Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-01-01
|
| Series: | BMC Gastroenterology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12876-017-0736-0 |
| _version_ | 1818203261711155200 |
|---|---|
| author | Renger G. Tiessen Ciara A. Kennedy Bradley T. Keller Nancy Levin Lisette Acevedo Bronislava Gedulin Andre A. van Vliet Alejandro Dorenbaum Melissa Palmer |
| author_facet | Renger G. Tiessen Ciara A. Kennedy Bradley T. Keller Nancy Levin Lisette Acevedo Bronislava Gedulin Andre A. van Vliet Alejandro Dorenbaum Melissa Palmer |
| author_sort | Renger G. Tiessen |
| collection | DOAJ |
| description | Abstract Background Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). Methods Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). Results Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6–3.2 times higher in HVs (643.73–1239.3 μmol/24 h) and ~8 times higher in T2DM (1786.0 μmol/24 h) than with placebo (HVs: 386.93 μmol/24 h; T2DM: 220.00 μmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3–5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. Conclusions Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013). |
| first_indexed | 2024-12-12T03:22:32Z |
| format | Article |
| id | doaj.art-3d128a07b8274c4e9e7f28c5bb378c0b |
| institution | Directory Open Access Journal |
| issn | 1471-230X |
| language | English |
| last_indexed | 2024-12-12T03:22:32Z |
| publishDate | 2018-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Gastroenterology |
| spelling | doaj.art-3d128a07b8274c4e9e7f28c5bb378c0b2022-12-22T00:40:08ZengBMCBMC Gastroenterology1471-230X2018-01-0118111710.1186/s12876-017-0736-0Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trialRenger G. Tiessen0Ciara A. Kennedy1Bradley T. Keller2Nancy Levin3Lisette Acevedo4Bronislava Gedulin5Andre A. van Vliet6Alejandro Dorenbaum7Melissa PalmerEarly Development Services, Pharmaceutical Research Associates (PRA) Health SciencesLumena Pharmaceuticals Inc. (part of the Shire group of companies)Lumena Pharmaceuticals Inc. (part of the Shire group of companies)Lumena Pharmaceuticals Inc. (part of the Shire group of companies)Lumena Pharmaceuticals Inc. (part of the Shire group of companies)Lumena Pharmaceuticals Inc. (part of the Shire group of companies)Early Development Services, Pharmaceutical Research Associates (PRA) Health SciencesLumena Pharmaceuticals Inc. (part of the Shire group of companies)Abstract Background Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). Methods Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). Results Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6–3.2 times higher in HVs (643.73–1239.3 μmol/24 h) and ~8 times higher in T2DM (1786.0 μmol/24 h) than with placebo (HVs: 386.93 μmol/24 h; T2DM: 220.00 μmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3–5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. Conclusions Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).http://link.springer.com/article/10.1186/s12876-017-0736-0Apical sodium-dependent bile acid transporterBile acidsClinical pharmacologyNon-alcoholic steatohepatitisNon-alcoholic fatty liver diseasePhase 1 clinical trial |
| spellingShingle | Renger G. Tiessen Ciara A. Kennedy Bradley T. Keller Nancy Levin Lisette Acevedo Bronislava Gedulin Andre A. van Vliet Alejandro Dorenbaum Melissa Palmer Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial BMC Gastroenterology Apical sodium-dependent bile acid transporter Bile acids Clinical pharmacology Non-alcoholic steatohepatitis Non-alcoholic fatty liver disease Phase 1 clinical trial |
| title | Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial |
| title_full | Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial |
| title_fullStr | Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial |
| title_full_unstemmed | Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial |
| title_short | Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial |
| title_sort | safety tolerability and pharmacodynamics of apical sodium dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus a randomised placebo controlled trial |
| topic | Apical sodium-dependent bile acid transporter Bile acids Clinical pharmacology Non-alcoholic steatohepatitis Non-alcoholic fatty liver disease Phase 1 clinical trial |
| url | http://link.springer.com/article/10.1186/s12876-017-0736-0 |
| work_keys_str_mv | AT rengergtiessen safetytolerabilityandpharmacodynamicsofapicalsodiumdependentbileacidtransporterinhibitionwithvolixibatinhealthyadultsandpatientswithtype2diabetesmellitusarandomisedplacebocontrolledtrial AT ciaraakennedy safetytolerabilityandpharmacodynamicsofapicalsodiumdependentbileacidtransporterinhibitionwithvolixibatinhealthyadultsandpatientswithtype2diabetesmellitusarandomisedplacebocontrolledtrial AT bradleytkeller safetytolerabilityandpharmacodynamicsofapicalsodiumdependentbileacidtransporterinhibitionwithvolixibatinhealthyadultsandpatientswithtype2diabetesmellitusarandomisedplacebocontrolledtrial AT nancylevin safetytolerabilityandpharmacodynamicsofapicalsodiumdependentbileacidtransporterinhibitionwithvolixibatinhealthyadultsandpatientswithtype2diabetesmellitusarandomisedplacebocontrolledtrial AT lisetteacevedo safetytolerabilityandpharmacodynamicsofapicalsodiumdependentbileacidtransporterinhibitionwithvolixibatinhealthyadultsandpatientswithtype2diabetesmellitusarandomisedplacebocontrolledtrial AT bronislavagedulin safetytolerabilityandpharmacodynamicsofapicalsodiumdependentbileacidtransporterinhibitionwithvolixibatinhealthyadultsandpatientswithtype2diabetesmellitusarandomisedplacebocontrolledtrial AT andreavanvliet safetytolerabilityandpharmacodynamicsofapicalsodiumdependentbileacidtransporterinhibitionwithvolixibatinhealthyadultsandpatientswithtype2diabetesmellitusarandomisedplacebocontrolledtrial AT alejandrodorenbaum safetytolerabilityandpharmacodynamicsofapicalsodiumdependentbileacidtransporterinhibitionwithvolixibatinhealthyadultsandpatientswithtype2diabetesmellitusarandomisedplacebocontrolledtrial AT melissapalmer safetytolerabilityandpharmacodynamicsofapicalsodiumdependentbileacidtransporterinhibitionwithvolixibatinhealthyadultsandpatientswithtype2diabetesmellitusarandomisedplacebocontrolledtrial |