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Reference Library HomeA Phase I/II Trial of High-Dose Erythropoietin in Extremely Low Birth Weight Infants: Pharmacokinetics and Safety
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Date Posted: Tuesday, September 23rd, 2008
| Pediatrics. 2008 Aug;122(2):383-391 Juul SE, McPherson RJ, Bauer LA, Ledbetter KJ, Gleason CA, Mayock DE Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA |
| Abstract Here |
| Summary |
| Although extremely low-birth-weight (ELBW) infants now survive, 36-48% have severe neurodevelopmental impairment. The risk of sustaining brain injury is most acute during the transition from intrauterine to extrauterine life, with >50% of intracranial hemorrhages (ICHs) occurring before day 1 of life and >90% by day 4. In animal models, high-dose recombinant erythropoietin (rEPO) is neuroprotective against long-term and short-term sequelae of brain injury. In the present open-label, prospective, dose-escalation phase I/II study, Juul and colleagues tested the safety and determined the pharmacokinetics of high-dose rEPO in ELBW infants during the first 3 d of life. Inclusion criteria were gestational age of ≤28 weeks gestation, birth weigh of ≤1000 g, consent obtained at <24 h of age, and an umbilical catheter in place. The concurrent control patients met the criteria but were not approached before 24 h of age, had no central arterial access, or consent given for only data collection. Thirty study patients (10 per group) received 1 of 3 dosages of rEPO (500, 1000, or 2500 U/kg intravenously) at 24-hour intervals beginning on day 1 of age. Blood samples were collected at defined intervals to determine pharmacokinetic and safety parameters. Only clinical data were obtained from control patients. The two groups had similar demographic baseline characteristics. High-dose rEPO followed nonlinear pharmacokinetics. As the rEPO dosage increased, disproportionately larger increases in the area under plasma concentration versus time curve were noted. The mean baseline rEPO concentration was 74.5 mU/mL, in a range from undetectable to 546 mU/mL. The mean EPO concentrations 30 min after rEPO infusion were 5973 ± 266, 12,291 ± 403, and 34,197 ± 1641 mU/mL after 500, 1000, or 2500 U/kg, respectively. Analysis of peak and trough concentrations of EPO indicated that the steady-state EPO concentrations were reached by the second dose (ie, within 24-48 h) for all three dosages studied. No unexpected serious adverse events developed. During treatment, the arterial blood pressures did not differ between the groups nor did the control and study infants differ in the incidence of ICH, periventricular leukomalacia, retinopathy of prematurity or need for laser eye surgery, necrotizing enterocolitis, and acute and chronic respiratory problems. Most infants in both groups had patent ductus arteriosus, with no difference between groups. Serious infections were common in both groups during hospitalization. Four control infants and 3 study infants (one in each dosage group) died during the neonatal period. Hospital stays for survivors were 27-231 d for controls and 24-159 for rEPO-treated infants. High-dose rEPO had no significant effect on any laboratory parameter. rEPO-treated infants received 5.2 ± 3.4 transfusions compared with 4.6 ± 4.0 for controls. No blood cell line abnormalities occurred in the rEPO-treated patients nor did the study and control patients differ in liver and renal function tests. Early high-dose rEPO is well tolerated by ELBW infants. rEPO dosages of 1000 and 2500 U/kg reached neuroprotective serum levels. Additional studies are needed to determine whether peak concentration or overall exposure is the basis of the neuroprotective effects of high-dose rEPO. |