Abstract
Background
Neonatal encephalopathy following perinatal asphyxia is a leading cause for neonatal death and disability, despite treatment with therapeutic hypothermia. 2-Iminobiotin is a promising neuroprotective agent additional to therapeutic hypothermia to improve the outcome of these neonates.
Methods
In an open-label study, pharmacokinetics and short-term safety of 2-iminobiotin were investigated in neonates treated with therapeutic hypothermia. Group A (n = 6) received four doses of 0.16 mg/kg intravenously q6h. Blood sampling for pharmacokinetic analysis and monitoring of vital signs for short-term safety analysis were performed. Data from group A was used to determine the dose for group B, aiming at an AUC0–48 h of 4800 ng*h/mL.
Results
Exposure in group A was higher than targeted (median AUC0–48 h 9522 ng*h/mL); subsequently, group B (n = 6) received eight doses of 0.08 mg/kg q6h (median AUC0–48 h 4465 ng*h/mL). No changes in vital signs were observed and no adverse events related to 2-iminobiotin occurred.
Conclusion
This study indicates that 2-iminobiotin is well tolerated and not associated with any adverse events in neonates treated with therapeutic hypothermia after perinatal asphyxia. Target exposure was achieved with eight doses of 0.08 mg/kg q6h. Optimal duration of therapy for clinical efficacy needs to be determined in future clinical trials.
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Acknowledgements
The authors thank Alwin Huitema for his critical appraisal of the PK analysis and Petra Lemmers for her assistance in extracting the data for the safety analysis. This study was supported by Neurophyxia BV with an unrestricted grant.
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L.M.A.F.: conception and design, acquisition of data, analysis and interpretation of data, drafting the manuscript; C.M.P.C.D.P.-S.: conception and design, data analysis, and critical revision of the manuscript for important intellectual content; A.B.: analysis and interpretation of data, critical revision of the manuscript for important intellectual content; H.T., T.C.G.E., F.v.B., C.M.A.R.: conception and design, critical revision of the manuscript for important intellectual content; P.V.: analysis and interpretation of data, critical revision of the manuscript for important intellectual content; F.G.: conception and design, acquisition of data, analysis and interpretation of data, critical revision of the manuscript for important intellectual content. L.M.A.F., C.M.P.C.D.P.-S., H.T., C.M.A.R., F.G., T.C.G.E., and F.v.B. were involved in drafting the concept and design of the study and in drafting the final protocol. C.M.P.C.D.P.-S. and H.T. advised on the study protocol and supplied several other documents required for ethics committee approval. L.M.A.F. and F.G. were involved in patient inclusion and study management. P.V. performed the pharmacokinetic analysis and advised on the 2-IB dose used for this study. L.M.A.F., A.B., and F.G. performed the safety analysis. L.M.A.F. drafted the manuscript; the other authors provided critical revision of the intellectual content. All authors read and approved the final manuscript.
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C.M.P.C.D.P.-S., F.v.B., and F.G. are the inventors of 2-iminobiotin as a neuroprotective agent in neonates with hypoxic–ischemic encephalopathy. C.M.P.C.D.P.-S. and H.T. are shareholders and consultants of Neurophyxia BV. P.V. is employed at LAP&P Consultants BV. The other authors declare no competing interests.
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Favié, L.M.A., Peeters-Scholte, C.M.P.C.D., Bakker, A. et al. Pharmacokinetics and short-term safety of the selective NOS inhibitor 2-iminobiotin in asphyxiated neonates treated with therapeutic hypothermia. Pediatr Res 87, 689–696 (2020). https://doi.org/10.1038/s41390-019-0587-1
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DOI: https://doi.org/10.1038/s41390-019-0587-1
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