Kim Annink

206 Chapter 9 Van Kesteren et al. found an interindividual variability of 60% for allopurinol clearance (27). In the current study, physiological processes were incorporated by adding body weight as a descriptor for body size. Despite this, there is still an interindividual variability of 35% in allopurinol clearance. In addition to allopurinol PK, we also estimated oxypurinol PK parameters. Oxypurinol clearance was estimated to be 0.31 L/h for a 3.5 kg infant. Since oxypurinol shows an equal ability in inhibiting xanthine-oxidase and has a relatively long half-life, the PK of oxypurinol is responsible for much of the pharmacological activity of allopurinol. An interindividual variability of 76% for clearance of oxypurinol was found. This large interindividual variability of oxypurinol is probably caused by the outlier. Furthermore, the differences can be explained because of the different study populations. In the study of van Kesteren et al. the study population had more severe perinatal asphyxia and HIE and in the ALBINO trial also infants with mild HIE were included because the decision to include infants had to be made much earlier after birth when the degree of HIE cannot be assessed with certainty. The risk of renal failure was therefore higher in the previous studies which might explain the lower clearance. Additionally, in the ALBINO trial therapeutic hypothermia might have had an effect on the PK of allopurinol. Multi-organ failure is common in infants with moderate to severe perinatal asphyxia and may have an impact on PK in infants with HIE (28,35). Multi-organ failure, such as hepatic failure due to hepatocyte necrosis and renal failure due to acute tubular necrosis, can reduce the clearance of drugs (35). As mentioned before, therapeutic hypothermia might also influence the pharmacokinetics of allopurinol. Van den Broek et al. reviewed the literature on the effect of therapeutic hypothermia on the PK of different drugs and found that absorption can be prolonged, the volume of distribution can be altered, i.e. by a lower pH or altered protein binding capacity, and clearance can be reduced (28). Therapeutic hypothermia can result in decreased cardiac output and increased vascular resistance leading to impaired liver and kidney perfusion (36). Also, the activity of liver enzymes and transporters that are important for hepatic clearance can be altered by hypothermia, as well as active tubular secretion (36,37). Favie et al.