Kim Annink

194 Chapter 9 ABSTRACT Background: Despite therapeutic hypothermia, hypoxic-ischemic encephalopathy (HIE) following perinatal asphyxia remains a major cause of morbidity and mortality. Allopurinol, a xanthine-oxidase inhibitor reducing superoxide formation, might offer add-on neuroprotection. The neuroprotective effect of allopurinol is currently investigated in the randomized placebo-controlled double-blinded ALBINO trial (NCT03162653). The aim of this sub-study was the pharmacokinetic evaluation of the allopurinol dosing regimen in the ALBINO trial. Methods: In the ALBINO trial, infants received a first dose of allopurinol or placebo within 45 minutes after birth (20mg/kg) and in case of hypothermia a second dose (10mg/kg) 12 hours later. A population pharmacokinetic model was developed for allopurinol and oxypurinol using nonlinear mixed effects modeling (NONMEM, version 7.3). A one-compartment model for allopurinol and oxypurinol was used to describe total body clearance (CL) and volume of distribution (Vd) in neonates normalized to a weight of 3.5kg. The model was used to evaluate whether >66% of patients reached the pre-specified target area under the curve (AUC) between 0-12 hours (43.5mg/L*h for allopurinol and 26.5mg/L*h for oxypurinol). Results: For this preliminary analysis, fifteen patients who received allopurinol were evaluated. The allopurinol target AUC was reached in all patients. The oxypurinol target AUC was reached in 66.6% of the cooled infants and 100% of the non-cooled infants. The CL of allopurinol was 0.339L/h and of oxypurinol 0.377L/h for an infant of 3.5kg. The Vd of allopurinol was 3.55L and of oxypurinol 5.51L for an infant of 3.5kg. Conclusion: The dosing regimen used in the ALBINO trial was adequate as the pre- specified target exposure was met.