A Phase IIa Clinical Trial of 2-Iminobiotin for the Treatment of Birth Asphyxia in DR Congo, a Low-Income Country.

AIM: The main burden of hypoxic-ischemic encephalopathy falls in low-income countries. 2-Iminobiotin, a selective inhibitor of neuronal and inducible nitric oxide synthase, has been shown to be safe and effective in preclinical studies of birth asphyxia. Recently, safety and pharmacokinetics of 2-iminobiotin treatment on top of hypothermia has been described. Since logistics and the standard of medical care are very different in low-resource settings, the aim of this study was to investigate safety and pharmacokinetics of Two-IminoBiotin in the Democratic Republic of Congo (TIBC). METHODS: Near-term neonates, born in Kinshasa, Democratic Republic of Congo, with a Thompson score ≥ 7 were eligible for inclusion. Excluded were patients with (1) inability to insert an umbilical venous catheter for administration of the study drug; (2) major congenital or chromosomal abnormalities; (3) birth weight < 1800 g; (4) clear signs of infection; and (5) moribund patients. Neonates received six infusions of 2-iminobiotin 0.16 mg/kg started within 6 h after birth, with 4-h intervals, targeting an AUC0-4h of 365 ng*h/mL. Safety, defined as vital signs, the need for clinical intervention after administration of study drug, occurrence of (serious) adverse events, and pharmacokinetics were assessed. RESULTS: After parental consent, seven patients were included with a median Thompson score of 10 (range 8-16). No relevant changes in vital signs were observed over time. There was no need for clinical intervention due to administration of study drug. Three patients died, two after completing the study protocol, one was moribund at inclusion and should not have been included. Pharmacokinetic data of 2-iminobiotin were best described using a two-compartment model. Median AUC0-4h was 664 ng*h/mL (range 414-917). No safety issues attributed to the administration of 2-iminobiotin were found. CONCLUSION: The present dosing regimen resulted in higher AUCs than targeted, necessitating a change in the dose regimen in future efficacy trials. No adverse effects that could be attributed to the use of 2-iminobiotin were observed. EudraCT number 2015-003063-12.

Pharmacokinetics and short-term safety of the selective NOS inhibitor 2-iminobiotin in asphyxiated neonates treated with therapeutic hypothermia.

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.