Developmental differences in erythropoietin pharmacokinetics: increased clearance and distribution in fetal and neonatal sheep.
Although erythropoietin (Ep) is considered the primary hormone responsible for erythrocyte production throughout development, the administration of recombinant human Ep (rhEp) to premature human neonates has, thus far, been ineffective in the prevention and treatment of their anemia. To determine if developmental pharmacokinetic differences might in part be responsible for this lack of efficacy, Ep pharmacokinetic studies were carried out in four groups of sheep: late gestation fetal, neonatal, adult and pregnant. After i.v. bolus injection of tracer amounts of the biologically active [125I]rhEp, plasma [125I]rhEp was measured using a sensitive and specific Ep immunoprecipitation assay. Pharmacokinetic parameters were derived using noncompartmental system analysis. Significantly greater clearances, shorter half-lives, shorter residence times, greater distribution volumes and greater Ep production rates were found in the fetal and neonatal groups compared to pregnant and nonpregnant adults (P less than .01). These developmental differences likely reflect more rapid metabolism and greater distribution of Ep in less mature individuals. As such, they could result in a reduction in Ep's erythropoietic effect similar to that reported in premature infants. We speculate that treatment of anemic premature neonates using rhEp doses shown to be effective in adults may be inadequate.
Widness
J A
JA
Department of Pediatrics, College of Medicine, University of Iowa, Iowa City.
Veng-Pedersen
P
P
Modi
N B
NB
Schmidt
R L
RL
Chestnut
D H
DH
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D005314:Embryonic and Fetal Development; D004921:Erythropoietin / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D011247:Pregnancy; D012756:Sheep; D014018:Tissue Distribution
D004921:Erythropoietin