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

Author(s): Ewoud-Jan van Hoogdalem, Cacha M.P.C.D. Peeters-Scholte, Paul W.T.J. Leufkens, Jan Hartstra, Jan J. van Lier, Leo G.J. de Leede*

Journal Name: Current Clinical Pharmacology

Volume 15 , Issue 2 , 2020

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Graphical 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.

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

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Article Details

Year: 2020
Page: [152 - 163]
Pages: 12
DOI: 10.2174/1574884714666191017111109

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