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
Continued as Current Reviews in Clinical and Experimental Pharmacology

Volume 15 , Issue 2 , 2020


Graphical Abstract:


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.

[1]
Yıldız EP, Ekici B, Tatlı B. Neonatal hypoxic ischemic encephalopathy: An update on disease pathogenesis and treatment. Expert Rev Neurother 2017; 17(5): 449-59.
[http://dx.doi.org/10.1080/14737175.2017.1259567] [PMID: 27830959]
[2]
Ahearne CE, Boylan GB, Murray DM. Short and long term prognosis in perinatal asphyxia: An update. World J Clin Pediatr 2016; 5(1): 67-74.
[http://dx.doi.org/10.5409/wjcp.v5.i1.67] [PMID: 26862504]
[3]
Lawn JE, Cousens S, Zupan J. Lancet neonatal survival steering team. 4 million neonatal deaths: When? Where? Why? Lancet 2005; 365(9462): 891-900.
[http://dx.doi.org/10.1016/S0140-6736(05)71048-5] [PMID: 15752534]
[4]
UNICEF, WHO, World Bank Group and United Nations. Levels and Trends in Child Mortality Report 2017.
[5]
Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; (1): CD003311
[http://dx.doi.org/10.1002/14651858.CD003311.pub3] [PMID: 23440789]
[6]
Bel Fv, Groenendaal F. Drugs for neuroprotection after birth asphyxia: Pharmacologic adjuncts to hypothermia. Semin Perinatol 2016; 40(3): 152-9.
[http://dx.doi.org/10.1053/j.semperi.2015.12.003] [PMID: 26794492]
[7]
Montaldo P, Pauliah SS, Lally PJ, Olson L, Thayyil S. Cooling in a low-resource environment: lost in translation. Semin Fetal Neonatal Med 2015; 20(2): 72-9.
[http://dx.doi.org/10.1016/j.siny.2014.10.004] [PMID: 25457083]
[8]
Biselele T, Bambi J, Naulaers G, et al. Observational study shows that it is feasible to provide neuroprotective treatment for neonatal encephalopathy in low-income countries. Acta Paediatr 2018; 107(8): 1345-9.
[http://dx.doi.org/10.1111/apa.14263] [PMID: 29424938]
[9]
Lancet T. Out-of-hospital cardiac arrest: A unique medical emergency. Lancet 2018; 391(10124): 911.
[http://dx.doi.org/10.1016/S0140-6736(18)30552-X] [PMID: 29536841]
[10]
Delhomme C, Njeim M, Varlet E, et al. Automated external defibrillator use in out-of-hospital cardiac arrest: Current limitations and solutions. Arch Cardiovasc Dis 2019; 112(3): 217-22.
[http://dx.doi.org/10.1016/j.acvd.2018.11.001] [PMID: 30594573]
[11]
Buanes EA, Gramstad A, Søvig KK, et al. Cognitive function and health-related quality of life four years after cardiac arrest. Resuscitation 2015; 89: 13-8.
[http://dx.doi.org/10.1016/j.resuscitation.2014.12.021] [PMID: 25596374]
[12]
Green CR, Botha JA, Tiruvoipati R. Cognitive function, quality of life and mental health in survivors of our-of-hospital cardiac arrest: A review. Anaesth Intensive Care 2015; 43(5): 568-76.
[http://dx.doi.org/10.1177/0310057X1504300504] [PMID: 26310406]
[13]
Fan X, van Bel F. Pharmacological neuroprotection after perinatal asphyxia. J Matern Fetal Neonatal Med 2010; 23(Suppl. 3): 17-9.
[http://dx.doi.org/10.3109/14767058.2010.505052] [PMID: 20695757]
[14]
Favié LMA, Cox AR, van den Hoogen A, et al. Nitric Oxide Synthase inhibition as a neuroprotective strategy following hypoxic-ischemic encephalopathy: Evidence from animal studies. Front Neurol 2018; 9: 258.
[http://dx.doi.org/10.3389/fneur.2018.00258] [PMID: 29725319]
[15]
Zitta K, Peeters-Scholte C, Sommer L, et al. 2-Iminobiotin superimposed on hypothermia protects human neuronal cells from hypoxia-induced cell damage: An in vitro study. Front Pharmacol 2018; 8: 971.
[http://dx.doi.org/10.3389/fphar.2017.00971] [PMID: 29358921]
[16]
Bjorkman ST, Ireland Z, Fan X, et al. Short-term dose-response characteristics of 2-iminobiotin immediately postinsult in the neonatal piglet after hypoxia-ischemia. Stroke 2013; 44(3): 809-11.
[http://dx.doi.org/10.1161/STROKEAHA.112.677922] [PMID: 23362078]


open access plus

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 2
Year: 2020
Published on: 17 October, 2019
Page: [152 - 163]
Pages: 12
DOI: 10.2174/1574884714666191017111109

Article Metrics

PDF: 25
HTML: 1