Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

Abstract

OBJECTIVE: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000–10 000 U/L; area under the curve = 117 000–140 000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

“…This high‐dose rhEPO in rodents was equivalent to that in preterm infants given at a high dose of 1,000 to 2,500U/kg 20. Based on those results from neonatal rodent brain injury models, clinical studies showed that high‐dose rhEPO (2,500–3,000U/kg) administered after birth was well tolerated in preterm and term infants14, 20, 33, 37, 42 and conferred neuroprotection 16, 36. In a previous study using low‐dose rhEPO to prevent anemia in preterm infants, it was observed that preterm infants with rhEPO treatment also had significant neurodevelopmental improvement 38.…”

“…EPO produced in the central nervous system7 is upregulated after insult and plays a role in neuroprotection 8, 9, 10, 11. Experimental studies have reported that rhEPO possesses neuroprotective properties in different neonatal brain injury animal models,12, 13 and clinical studies have shown that rhEPO treatment reduces brain injury and the incidence of neurological disabilities in infants 8, 14, 15, 16, 17. In addition, improved neurodevelopmental outcomes have been observed in preterm infants with anemia after rhEPO treatment 17, 18, 19, 20.…”

“…It has been shown that serum rhEPO concentrations are positively correlated with the degree of maturation during mental development in preterm infants,21 and high‐dose rhEPO (2,500U/kg) is well tolerated by preterm infants, causing no excess morbidity or mortality 14, 20. However, it is still a significant concern to use high‐dose rhEPO in very preterm infants because this might increase the potential risk of ROP 19, 22, 23.…”

High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial

“…[10][11][12][13][14][15] In a phase I trial of combined Epo treatment with hypothermia, we found that Epo (1000 U/kg given intravenously) provided the optimal plasma Epo levels consistent with animal studies of neuroprotection. 16 Although the study was not designed to evaluate efficacy, patients who received multiple high doses of Epo exhibited a lower rate of death or moderate/ severe disability at 22 months (4.5%) 17 than had been expected based on studies of infants with similar entry criteria who received hypothermia alone (44%-51%). [4][5][6]8 Two small trials in China and Egypt found that Epo therapy improved short-term neurologic outcomes after HIE.…”

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

“…ЭПО экспрессируется в голов-ном мозге человека и животных, особенно в астроцитах и микроглии, на ранних стадиях жизни и поэтому необ-ходим для развития мозга, но постепенно снижается после рождения [89]. Исследования показали, что при-менение высоких доз ЭПО у новорожденных крыс с ГИП приводит к гистологическим и функциональным (вклю-чая такие, как пространственная память) улучшениям, также отмечается дозозависимое уменьшение объема инфаркта [90][91][92]. Опубликованы данные по крайней мере трех пилотных клинических исследований в Китае, Египте и США, которые характеризовались относительно небольшим количеством участников и показали сниже-ние тяжелых исходов при ГИП в случае использования ЭПО, а также его безопасность [93][94][95].…”