title: Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-β-Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant.
abstract: 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.
authors.affiliation: Virtual Proof of Concept Discovery Performance Unit (VPoC DPU), GlaxoSmithKline King of Prussia, PA, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brigandi
authors.affiliation: VPoC DPU, GlaxoSmithKline Research Triangle Park, NC, USA.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Russ
authors.affiliation: Virtual Proof of Concept Discovery Performance Unit (VPoC DPU), GlaxoSmithKline King of Prussia, PA, USA.
authors.forename: Chantal
authors.initials: C
authors.lastname: Petit
authors.affiliation: Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline Research Triangle Park, NC, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Global Formulation Development, GlaxoSmithKline Collegville, PA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Croy
authors.affiliation: Formerly of Nucleus Network Melbourne, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Hodsman
authors.affiliation: Global Formulation Development, GlaxoSmithKline Collegville, PA, USA.
authors.forename: Fran
authors.initials: F
authors.lastname: Muller
keywords: NK-1 receptor antagonist; SBE7-β-cyclodextrin; hemolysis; intravenous; vestipitant