Title:First-in-Human Study of the Safety, Tolerability, Pharmacokinetics and - Preliminary Dynamics of Neuroprotectant 2-Iminobiotin in Healthy Subjects
VOLUME: 15 ISSUE: 2
Author(s):Ewoud-Jan van Hoogdalem, Cacha M.P.C.D. Peeters-Scholte, Paul W.T.J. Leufkens, Jan Hartstra, Jan J. van Lier and Leo G.J. de Leede*
Affiliation:Scientific Affairs – Clinical Pharmacology, PRA Health Sciences, Groningen, Neurophyxia B.V., 's-Hertogenbosch, Neurophyxia B.V., 's-Hertogenbosch, Early Development Services, PRA Health Sciences, Groningen, Early Development Services, PRA Health Sciences, Groningen, Neurophyxia B.V., 's-Hertogenbosch
Keywords:2-iminobiotin, healthy subjects, nitric oxide synthase, pharmacokinetics, neuroprotection, birth asphyxia, cardiac
arrest.
Abstract:Background: 2-iminobiotin (2-IB) is an investigational neuroprotective agent in development
for the reduction of brain cell injury after cerebral hypoxia-ischemia.
Objective: The present first-in-human study evaluated the safety, tolerability, pharmacokinetics
(PK) and -dynamics (PD) of 2-IB in healthy male subjects, intravenously infused with or without
Captisol® as a solubilizing agent.
Methods: This randomized, double-blind, placebo-controlled, dose-escalation study was executed
in 2 groups of 9 healthy male subjects. A single dose of 2-IB 0.6 mg/kg or placebo was infused over
periods between 15 min and 4 h, and repeated doses escalating from 0.6 mg/kg to 12 mg/kg, or
placebo were infused every 4 h for 6 administrations in total.
Results: Single and multiple doses of 2-IB up to 6 doses of 6 mg/kg with and without Captisol®
were safe and well-tolerated in healthy male subjects. 2-IB proved to be a high-clearance drug with
a volume of distribution slightly exceeding total body water volume, and with linear PK that appeared
not to be affected by the presence of Captisol®.
Conclusion: Sulfobutyletherbeta-cyclodextrin (SBECD) in Captisol® had a low-clearance profile
with a small volume of distribution, with time-independent PK. Preliminary PD characterization of
repeated iv dosing of 2-IB in an acute peripheral hypoxic ischemia model in healthy subjects did
not reveal any notable effects of 2-IB, noting that this model was not selected to guide efficacy in
the currently pursued indication of cerebral hypoxia-ischemia.
