Peter Vis1, Floris Groenendaal2,3, Laurent M A Favié4,5, Cacha M P C D Peeters-Scholte6, Anouk Bakker2, Huibert Tjabbes6, Toine C G Egberts7,8, Frank van Bel2,3, Carin M A Rademaker7. 1. LAP&P Consultants BV, Leiden, the Netherlands. 2. Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands. 3. UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands. 4. Department of Clinical Pharmacy, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands. l.m.a.favie@umcutrecht.nl. 5. Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands. l.m.a.favie@umcutrecht.nl. 6. Neurophyxia B.V., 's-Hertogenbosch, the Netherlands. 7. Department of Clinical Pharmacy, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands. 8. Department of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
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.
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.
Authors: Laurent M A Favié; Timo R de Haan; Yuma A Bijleveld; Carin M A Rademaker; Toine C G Egberts; Debbie H G M Nuytemans; Ron A A Mathôt; Floris Groenendaal; Alwin D R Huitema Journal: Clin Pharmacol Ther Date: 2020-06-27 Impact factor: 6.875
Authors: Vu Thao-Vi Dao; Mahmoud H Elbatreek; Thomas Fuchß; Ulrich Grädler; Harald H H W Schmidt; Ajay M Shah; Alan Wallace; Richard Knowles Journal: Handb Exp Pharmacol Date: 2021