Kim Annink

208 Chapter 9 we were not able to investigate whether the outlier in the ALBINO trial had a polymorphism in hAOX1. This pilot study had some limitations. The sample size for this pharmacokinetic study was rather small to evaluate the effect of therapeutic hypothermia and disease severity as covariates in the model. Small sample sizes with limited data points are a well- known problem in pediatrics (40). Therefore, the population approach is preferable because it allows to analyze limited data with unequal distribution of samples over time and between individuals. The nonlinear mixed effect model allows to investigate the population pharmacokinetics but also takes into account that the samples come from different individuals (41). Another limitation is that the ALBINO trial is still ongoing, so only limited clinical characteristics were available to prevent unblinding. We recommend to combine the pharmacokinetic results of the ALBINO trial with the historical data of van Kesteren et al. (27) to increase the sample size and investigate the effect of covariates on the pharmacokinetics of allopurinol and oxypurinol. This allows us to draw conclusions about the effect of therapeutic hypothermia and disease severity, and also of maturation and organ recovery, on the pharmacokinetics of allopurinol in neonates with HIE. CONCLUSION Dosing regimens in the ALBINO trial are adequate as predefined in the study protocol, also during hypothermia. No dosing adaptations are necessary. ACKNOWLEDGMENTS The bioanalysis of allopurinol and oxypurinol was performed at ABL on the request of the industry partner of the ALBINO consortium to meet Good Laboratory Practice standards according to EMA and FDA requirements. ABL received compensation for their work from the grant from the European Union. FUNDING The ALBINO trial is funded under the Horizon 2020 Framework Program of the European Union, call H2020-PHC-2015-two-stage, grant 667224. DISCLOSURE None of the authors had a conflict of interest to disclose.