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Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-β-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant

Vestipitant is a potent and selective neurokinin 1 (NK-1) receptor antagonist that was investigated as a potential treatment for post-operative nausea and vomiting (PONV). A previous mannitol-based formulation of vestipitant was associated with hemolytic activity in preclinical studies. In an effort...

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Autores principales: Brigandi, Richard A, Russ, Steven F, Petit, Chantal, Johnson, Brendan, Croy, Scott, Hodsman, Peter, Muller, Fran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467239/
https://www.ncbi.nlm.nih.gov/pubmed/26097793
http://dx.doi.org/10.1002/cpdd.128
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author Brigandi, Richard A
Russ, Steven F
Petit, Chantal
Johnson, Brendan
Croy, Scott
Hodsman, Peter
Muller, Fran
author_facet Brigandi, Richard A
Russ, Steven F
Petit, Chantal
Johnson, Brendan
Croy, Scott
Hodsman, Peter
Muller, Fran
author_sort Brigandi, Richard A
collection PubMed
description Vestipitant is a potent and selective neurokinin 1 (NK-1) receptor antagonist that was investigated as a potential treatment for post-operative nausea and vomiting (PONV). A previous mannitol-based formulation of vestipitant was associated with hemolytic activity in preclinical studies. In an effort to reduce the hemolytic potential and develop an IV formulation of vestipitant that could be administered more rapidly, an IV formulation containing sulfobutylether-7-beta-cyclodextrin (SBE7-β-CD, Captisol™) was developed and tested in a phase 1 clinical study. This was a randomized, single-blind (subjects and investigator—blinded, sponsor-unblinded), placebo controlled, dose escalation study in healthy subjects in which 7 cohorts of 8 subjects per cohort received SBE7-β-CD -based vestipitant (2 mg/mL) or placebo (saline) in a 3:1 ratio (active:placebo) at different doses and infusion rates. The results demonstrated the ability to infuse up to 48 mg vestipitant in a 2 mg/mL formulation over 30 seconds with no evidence of hemolytic effects. Cohorts of subjects at lower doses and longer infusion duration (>1 minute) reported more AEs related to the infusion site than those at the higher doses and faster infusion rates.
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spelling pubmed-44672392015-06-17 Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-β-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant Brigandi, Richard A Russ, Steven F Petit, Chantal Johnson, Brendan Croy, Scott Hodsman, Peter Muller, Fran Clin Pharmacol Drug Dev Articles Vestipitant is a potent and selective neurokinin 1 (NK-1) receptor antagonist that was investigated as a potential treatment for post-operative nausea and vomiting (PONV). A previous mannitol-based formulation of vestipitant was associated with hemolytic activity in preclinical studies. In an effort to reduce the hemolytic potential and develop an IV formulation of vestipitant that could be administered more rapidly, an IV formulation containing sulfobutylether-7-beta-cyclodextrin (SBE7-β-CD, Captisol™) was developed and tested in a phase 1 clinical study. This was a randomized, single-blind (subjects and investigator—blinded, sponsor-unblinded), placebo controlled, dose escalation study in healthy subjects in which 7 cohorts of 8 subjects per cohort received SBE7-β-CD -based vestipitant (2 mg/mL) or placebo (saline) in a 3:1 ratio (active:placebo) at different doses and infusion rates. The results demonstrated the ability to infuse up to 48 mg vestipitant in a 2 mg/mL formulation over 30 seconds with no evidence of hemolytic effects. Cohorts of subjects at lower doses and longer infusion duration (>1 minute) reported more AEs related to the infusion site than those at the higher doses and faster infusion rates. Blackwell Publishing Ltd 2015-03 2014-05-26 /pmc/articles/PMC4467239/ /pubmed/26097793 http://dx.doi.org/10.1002/cpdd.128 Text en © 2014 The Authors. Clinical Pharmacology in Drug Development Published by The American College of Clinical Pharmacology http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Brigandi, Richard A
Russ, Steven F
Petit, Chantal
Johnson, Brendan
Croy, Scott
Hodsman, Peter
Muller, Fran
Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-β-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant
title Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-β-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant
title_full Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-β-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant
title_fullStr Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-β-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant
title_full_unstemmed Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-β-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant
title_short Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-β-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant
title_sort intravenous pharmacokinetics, local tolerability, and hemolysis of an sbe7-β-cyclodextrin formulation of the neurokinin-1 receptor antagonist vestipitant
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467239/
https://www.ncbi.nlm.nih.gov/pubmed/26097793
http://dx.doi.org/10.1002/cpdd.128
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