Kim Annink

196 Chapter 9 window” up to 4 hours after birth in the postnatal studies was probably too broad, since the peak of the superoxide formation is within 30-60 minutes after birth (25). Antenatal treatment with allopurinol was thought to prevent superoxide production already during the first minutes after birth, but it turned out to be difficult to select the infants prone for birth asphyxia-induced HIE based on fetal monitoring (21). We currently investigate the neuroprotective effect of allopurinol administered within 45 minutes after birth in moderately to severely asphyxiated neonates in a large phase III randomized controlled European trial, entitled “Effect of Allopurinol in addition to hypothermia for hypoxic ischemic Brain Injury on Neurocognitive Outcome” (ALBINO, EudraCT-No 2016-000222-19) (26). In the ALBINO trial, the area under the concentration curve (AUC) of allopurinol and oxypurinol following early allopurinol administration during therapeutic hypothermia was also investigated as pharmacokinetic outcome variable to ensure that target exposure is attained (26). Pharmacokinetics of allopurinol in (near-)term neonates with HIE has already been studied in earlier trials mentioned above and showed that two intravenous doses of 20mg/kg (within 4 hours after birth and 12 hours later) resulted in supratherapeutic doses without toxicity (18,19,27). However, all these patients were included before therapeutic hypothermia became standard of care and both asphyxia and therapeutic hypothermia affect pharmacokinetics (28). Therefore, the primary aim of this pharmacokinetic sub-study of the ALBINO trial was to determine whether the pre-defined target AUC of allopurinol (43.5 mg/L*h) and oxypurinol (26.5 mg/L*h) are met (27).