High-dose erythropoietin population pharmacokinetics in neonates with hypoxic-ischemic encephalopathy receiving hypothermia

Abstract

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 six 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 h of treatment (AUC48 h) 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 1,000 U/kg every 24 h for the first 2 d of therapy achieved the target AUC48 h 140,000 mU*h/ml. No neonate who received a lower dosing regimen achieved this target.

Conclusion: In neonates with HIE receiving hypothermia, Epo 1,000 U/kg every 24 h for the first 2 d of therapy resulted in consistent achievement of target exposures associated with neuroprotection in animal models.

Conflict of interest statement

Conflicts of Interest

The authors have no conflict of interest, real or perceived, to report.

Conflict of Interest: The authors have no conflict of interest, real or perceived, to report.

Figures

Figure 1

Observed vs. population predicted concentrations (a) and conditional weight residual vs. population predicted concentrations (b) for the final pharmacokinetic model. Solid line indicates the line of unity. Dashed line indicates loess smooth.

Figure 2

AUC48h (a) and Cmax after first dose (b) in neonates with HIE receiving hypothermia by Epo dosing regimen. Boxplots represent dosing regimens in the first 48 hours of 500 (n=6), 1000 (n=7), 2500 (n=8) U/kg every 48 hour (q48h) and 1000 U/kg every 24 hours (n=23; q24h). The dosing regimen of 250 U/kg every 48 hour (n=3) is not shown. Dashed lines reference target AUC48h 140,000 mU*h/ml and Cmax concentration 10,000 mU/ml.

Figure 3

Predicted erythropoietin concentration-time course during the first week of therapy in a typical study neonate with HIE receiving 1000 U/kg per the Phase I and Phase II dosing schedule. The dosing schedule was every 48h in the Phase I study (solid line) and every 24h for 3 doses followed by every 48h in the Phase II study (dashed line). The final population pharmacokinetic model was used to predict all concentrations for a neonate weighing 3.4 kg.