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First-in-Human Study of the Safety, Tolerability, Pharmacokinetics and - Preliminary Dynamics of Neuroprotectant 2-Iminobiotin in Healthy Subjects

[ Vol. 14 , Issue. ]

Author(s):

Ewoud-Jan van Hoogdalem, Cacha M.P.C.D. Peeters-Scholte, Paul W.T.J. Leufkens, Jan Hartstra, Jan Jaap van Lier and Leo G.J. de Leede* Pages 1-12 (12)

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 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 and Conclusion: 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 volume of distribution slightly exceeding total body water volume, and with linear PK that appeared not be affected by presence of Captisol®. Sulfobutylether-beta-cyclodextrin (SBECD) in Captisol® had a low-clearance profile with 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.

Keywords:

2-iminobiotin, healthy subjects, nitric oxide synthase, pharmacokinetics, neuroprotection, birth asphyxia, cardiac arrest

Affiliation:

Scientific Affairs – Clinical Pharmacology, Groningen, Netherlands; Neurophyxia B.V, `s-Hertogenbosch, Scientific Affairs – Early Development Services, Groningen, Netherlands; Neurophyxia B.V, `s-Hertogenbosch, Scientific Affairs – Early Development Services, Groningen, Netherlands; Neurophyxia B.V, `s-Hertogenbosch, Scientific Affairs – PRA Health Sciences, Groningen, Netherlands; Neurophyxia B.V, `s-Hertogenbosch, Scientific Affairs – PRA Health Sciences, Groningen, Netherlands; Neurophyxia B.V, `s-Hertogenbosch, Scientific Affairs – Early Development Services, Groningen, Netherlands; Neurophyxia B.V, `s-Hertogenbosch



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