Change in Erythropoietin Pharmacokinetics Following Hematopoietic Transplantation

Abstract

Pre-clinical studies have demonstrated that bone marrow ablation has a profound effect in decreasing erythropoietin (EPO) elimination. The study's objective was to determine in humans if EPO pharmacokinetics (PKs) are perturbed following bone marrow ablation. EPO PK studies were performed in eight subjects, aged 4 to 61 years, undergoing fully myeloablative hematopoietic stem cell transplantation. Serial PK studies using intravenous injection of recombinant human EPO (92 ±2.0 U/kg) (mean±SEM) were carried out during four periods of altered marrow integrity: baseline pre-ablation, post-ablation pre-transplant, early post-transplant pre-engraftment, and late posttransplant full engraftment. Compared with baseline, post-ablation pre-transplant and early posttransplant EPO PKs demonstrated declines in clearance increases in terminal elimination half-life of 36 and 95%, respectively. Clearance and half-life returned to baseline following full engraftment. The association of EPO elimination with decreased bone marrow activity in patients undergoing transplantation conclusively establishes the bone marrow as a key determinant of EPO elimination in humans.Erythropoietin (EPO), a 34-kDa glycoprotein hormone, has a dominant action in the regulation of erythrocyte production. 1 EPO exerts its biological effect in stimulating the proliferation and differentiation of erythroid progenitors by binding to specific cell-surface receptors (EPO-Rs) that are in greatest abundance on erythroid progenitors located primarily in the bone marrow. 2 EPO-Rs are also located on virtually all non-hematopoietic tissues and have diverse additional biologic effects. 3 There is a paucity of information regarding which organ(s) and tissue(s) are important in EPO metabolism and elimination. Previous in vivo studies demonstrated that the kidney and liver exert no measurable effect on EPO in vivo elimination. [4][5][6] Erythropoietic tissues in rats, e.g., bone marrow and spleen, have also been shown to rapidly metabolize EPO with tissue uptake and clearance directly correlated with the number of erythroid colony-forming units. 7 These pre-clinical in vivo studies are supported by in vitro studies demonstrating that EPO is rapidly degraded by ligand-specific EPO-R erythroid progenitors, 8,9 and by clinical studies in anemic patients with hypoplastic marrows manifesting high serum EPO levels relative to their hemoglobin (Hb) levels. [10][11][12] Correspondence: JA Widness (john-widness@uiowa.edu). CONFLICT OF INTERESTThe authors declared no conflict of interest. In adults, EPO has demonstrated nonlinear pharmacokinetic (PK) behavior, with EPO clearance decreasing as the administered EPO dose increases. [12][13][14] The half-life of EPO ranges from 4 to 8 h in healthy adults given therapeutic doses of EPO. 13 In very-low-birth-weight premature infants, EPO also manifests nonlinear PK behavior, with clearances approximately threefold greater than adults. 15 Notably premature and term infants also manifest proportionally greater red marrow spac...

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

“…57 Similar to previous neonatal studies, 28,29,58,59 we found that high- Epo appears to be primarily eliminated by receptor-mediated clearance. 31,62 As in previous reports, 32,33,58,63 we found that Epo followed nonlinear pharmacokinetics. As the dose of Epo increased twofold, fourfold, and 10-fold, the overall exposure to circulating Epo (AUC) increased 2.7, 7.1, and 17.8 times, respectively.…”

“…[31][32][33] Data analysis was conducted by using noncompartmental pharmacokinetic techniques. 34,35 The elimination rate constant (k) for the plasma data were derived by using linear regression to compute the slope of the ln plasma Epo concentration versus time data during the terminal portion of the curve.…”

Evidence of Receptor-Mediated Elimination of Erythropoietin by Analysis of Erythropoietin Receptor mRNA Expression in Bone Marrow and Erythropoietin Clearance During Anemia

“…Our previous studies provided significant evidence that bone marrow plays a major role in Epo elimination (Chapel et al, 2001a;Widness et al, 2007) and EpoR is up-regulated as a result of phlebotomy-induced anemia in sheep . Similarly, the present study showed an increase in Epo clearance 9 days after phlebotomy.…”

“…First, Epo's clearance shows transient perturbations in conjunction with large transient perturbations in endogenous Epo levels (Chapel et al, 2001b;Freise et al, 2007;Widness et al, 2007). Second, the Epo clearance is significantly reduced after busulfan-induced bone marrow ablation (Chapel et al, 2001a).…”

“…Although the mechanisms involved in Epo elimination and site of degradation are still not completely understood, several studies suggest that receptor-mediated elimination of Epo plays an important central role in its clearance (Chapel et al, 2001a,b;Widness et al, 2007).…”