Juul Sandra E, McPherson Ronald J, Bauer Larry A, Ledbetter Kelly J, Gleason Christine A, Mayock Dennis E
Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA.
Pediatrics. 2008 Aug;122(2):383-91. doi: 10.1542/peds.2007-2711.
High-dose recombinant erythropoietin is neuroprotective in animal models of neonatal brain injury. Extremely low birth weight infants are at high risk for brain injury and neurodevelopmental problems and might benefit from recombinant erythropoietin. We designed a phase I/II trial to test the safety and determine the pharmacokinetics of high-dose recombinant erythropoietin in extremely low birth weight infants.
In a prospective, dose-escalation, open-label trial, we compared 30 infants who were treated with high-dose recombinant erythropoietin with 30 concurrent control subjects. Eligible infants were <24 hours old, <or=1000 g birth weight, and <or=28 weeks of gestation and had an umbilical artery catheter in place. Each infant received 3 intravenous doses of 500, 1000, or 2500 U/kg at 24-hour intervals beginning on day 1 of age. Blood samples were collected at scheduled intervals to determine recombinant erythropoietin pharmacokinetics. Safety parameters were also evaluated. In the concurrent control group, only clinical data were collected.
Mean erythropoietin concentrations 30 minutes after recombinant erythropoietin infusion were 5973 +/- 266, 12291 +/- 403, and 34197 +/- 1641 mU/mL after 500, 1000, or 2500 U/kg, respectively. High-dose recombinant erythropoietin followed nonlinear pharmacokinetics as a result of decreasing clearance from the lowest dosage (17.3 mL/hour per kg for 500 U/kg) to the highest dosage (8.2 mL/hour per kg for 2500 U/kg). Steady state was achieved within 24 to 48 hours. Both 1000 and 2500 U/kg recombinant erythropoietin produced peak serum erythropoietin concentrations that were comparable to neuroprotective concentrations that previously were seen in experimental animals. No excess adverse events occurred in the recombinant erythropoietin-treated infants compared with control infants.
Early high-dose recombinant erythropoietin is well tolerated by extremely low birth weight infants, causing no excess morbidity or mortality. Recombinant erythropoietin dosages of 1000 and 2500 U/kg achieved neuroprotective serum levels.
高剂量重组促红细胞生成素在新生儿脑损伤动物模型中具有神经保护作用。极低出生体重儿发生脑损伤和神经发育问题的风险很高，可能会从重组促红细胞生成素中获益。我们设计了一项I/II期试验，以测试高剂量重组促红细胞生成素在极低出生体重儿中的安全性并确定其药代动力学。
在一项前瞻性、剂量递增、开放标签试验中，我们将30例接受高剂量重组促红细胞生成素治疗的婴儿与30例同期对照受试者进行了比较。符合条件的婴儿年龄小于24小时，出生体重小于或等于1000克，孕周小于或等于28周，且已放置脐动脉导管。从出生第1天开始，每个婴儿每隔24小时接受3次静脉注射，剂量分别为500、1000或2500 U/kg。按预定时间间隔采集血样以确定重组促红细胞生成素的药代动力学。还评估了安全参数。在同期对照组中，仅收集临床数据。
重组促红细胞生成素输注后30分钟，500、1000或2500 U/kg剂量组的促红细胞生成素平均浓度分别为5973±266、12291±403和34197±1641 mU/mL。由于清除率从最低剂量（500 U/kg时为17.3 mL/小时·千克）降至最高剂量（2500 U/kg时为8.2 mL/小时·千克），高剂量重组促红细胞生成素呈现非线性药代动力学。在24至48小时内达到稳态。1000和2500 U/kg的重组促红细胞生成素产生的血清促红细胞生成素峰值浓度与先前在实验动物中观察到的神经保护浓度相当。与对照婴儿相比，接受重组促红细胞生成素治疗的婴儿未出现过多不良事件。
极低出生体重儿对早期高剂量重组促红细胞生成素耐受性良好，未导致过多的发病率或死亡率。1000和2500 U/kg的重组促红细胞生成素剂量达到了神经保护血清水平。
