High-Dose Erythropoietin Population Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia

BACKGROUND: High-dose erythropoietin (Epo) is a promising neuroprotective treatment in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of high-dose Epo in this population to inform future dosing strategies. METHODS: We performed a population pharmacokinetic analysis of 47 neonates with HIE treated with hypothermia who received up to 6 doses of Epo in two previous clinical trials. We compared the ability of different dosing regimens to achieve the target neuroprotective Epo exposure levels determined from animal models of hypoxic-ischemia (i.e., area under the curve during the first 48 hours of treatment [AUC(48h)] 140,000 mU*h/ml). RESULTS: Birth weight scaled via allometry was a significant predictor of Epo clearance and volume of distribution (p<0.001). After accounting for birth weight, variation in Epo pharmacokinetics between neonates was low (CV% 20%). All 23 neonates who received 1000 U/kg every 24 h for the first 2 days of therapy achieved the target AUC(48h) 140,000 mU*h/ml. No neonate who received a lower dosing regimen achieved this target. CONCLUSIONS: In neonates with HIE receiving hypothermia, Epo 1000 U/kg every 24 hours for the first 2 days of therapy resulted in consistent achievement of target exposures associated with neuroprotection in animal models.