On target dosing: erythropoietin exposure in neonates with hypoxic-ischemic encephalopathy in the HEAL trial.

Background: The High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia demonstrated no neurodevelopmental benefit but was associated with a higher rate of serious adverse events (SAEs). Understanding if targeted Epo plasma exposures were achieved in the HEAL trial and if SAEs were associated with higher exposures would help future therapeutic programs of Epo as a candidate neuroprotective treatment.

Methods: Ancillary study of a subset of HEAL neonates who received Epo (1000 U/kg IV on days 1, 2, 3, 4, and 7) and had plasma drug concentrations measured. Within a Bayesian pharmacokinetic framework, the area under the curve during the first 48 h (AUC_48h) and 7 days (AUC_7d) of treatment was estimated. The % of neonates who achieved animal model neuroprotective targets of AUC_48h >140,000 mU*h/ml and AUC_7d >420,000 mU*h/ml was calculated. The relationship between AUC_7d and SAEs after study drug was evaluated using logistic regression.

Results: Among n = 89 neonates, variation in Epo exposure was low, and over 95% of neonates achieved the target AUC_48h and AUC_7d. No meaningful relationship was seen between AUC_7d and risk of SAE.

Conclusions: The Epo dosing strategy in the HEAL trial consistently achieved target plasma exposures. Higher exposures were not associated with SAEs.

Impact: In the HEAL randomized, placebo-controlled trial of high-dose erythropoietin (Epo) for neonates with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia, the Epo dosing strategy achieved animal model neuroprotective plasma exposure targets in >95% of neonates. This understanding further strengthens the HEAL trial's primary conclusion that Epo provides no additional benefit in neonates with HIE also receiving therapeutic hypothermia. While Epo treatment was associated with a higher rate of serious adverse events (SAEs) compared to placebo in the primary HEAL trial, higher plasma exposures of Epo were not associated with the risk of SAEs.