Pharmacokinetic tracer kinetics analysis of changes in erythropoietin receptor population in phlebotomy-induced anemia and bone marrow ablation.
ABSTRACT The objective was to study in vivo erythropoietin (Epo) progenitor cell surface receptors (EpoR) in the bone marrow (BM) after phlebotomy and bone marrow ablation.
Serial tracer interaction method experiments were conducted in adult sheep at baseline and after phlebotomy (PH) and ablation (AB). PH was done 10 days after phlebotomy (to 3-4 g/dl Hb), and the AB was done 8 days after a 3-day oral treatment with bulsulfan (11 mg/kg/day).
Bone marrow ablation changed the elimination from non-linear to linear, consistent with an abolition of the non-linear elimination via BM EpoRs. The phlebotomy increased the linear clearance of the ablated elimination pathway (from 63.6+/-12 to 126+/-64 ml/h/kg), consistent with an up-regulation of the erythroid progenitor BM-based EpoR pool, but did not change the clearance of the non-ablated elimination pathway (p>0.05). The EpoR pool size remaining after BM ablation was 7.4+/-2.7% of the pre-ablation pool.
Erythropoietin elimination via EpoR in the bone marrow was non-linear and increased following phlebotomy-induced anemia. This is consistent with an up-regulation of the erythropoietic EpoR pool in BM. Assuming that the elimination of Epo after BM ablation was via non-hematopoietic EpoR, then this post-ablation EpoR population was not significantly up-regulated by the phlebotomy.
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ABSTRACT: Recombinant human erythropoietin (rHuEPO; epoetin alfa), is a glycosylated hormone commonly used for the treatment of anemia associated with chronic kidney disease [1–4]. It is also indicated for the treatment of certain anemias associated with cancer, HIV infection, and for use in surgical situations to reduce allogeneic blood transfusion requirements. A number of studies have demonstrated that rHuEPO is well tolerated and effective at ameliorating anemia, restoring energy levels, and improving patient quality of life in these indications [5–7]. It has also been shown to reduce transfusions, a procedure that can carry inherent risks including transmission of infectious agents and iron overload. In addition, the blood supply is limited and transfusion-induced immune reactions can complicate organ transplantation, for example in patients with kidney transplants.12/2008: pages 115-140;
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ABSTRACT: Recombinant human erythropoietin (rHuEPO), such as the approved agents epoetin alfa and epoetin beta, has been used successfully for over 20 years to treat anemia in millions of patients. However, due to the relatively short half-life of the molecule (approximately 8 hours), frequent dosing may be required to achieve required hemoglobin levels. Therefore, a need was identified in some anemic patient populations for erythropoiesis stimulating agents with longer half-lives that required less frequent dosing. This need led to the development of second generation molecules which are modified versions of rHuEPO with improved pharma-cokinetic and pharmacodynamic properties such as darbepoetin alfa, a hyperglycosylated analog of rHuEPO, and pegzyrepoetin, a pegylated rHuEPO. Third generation molecules, such as peginesatide, which are peptide mimetics that have no sequence homology to rHuEPO have also recently been developed. The various molecular, pharmacokinetic, and pharmacodynamic properties of these and other erythropoiesis stimulating agents will be discussed in this review.Targets & therapy 01/2013; 7:161-174.
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ABSTRACT: The cloning of the EPO gene in the early 1980s allowed for the development of recombinant erythropoietins and analogues [erythropoiesis-stimulating agents (ESAs)], offering an alternative to transfusion as a method of raising haemoglobin (Hb) levels, which have been used for more than 20 years to treat anaemia in millions of anaemic patients. There are now a number of ESAs available worldwide for the treatment of anaemia, approved for different routes of administration (intravenous and subcutaneous) and dosing intervals (three times weekly, weekly, biweekly and monthly). In this review, we discuss the pharmacokinetic characteristics, including absorption, distribution and elimination processes, across the different ESAs. Incomplete and slow lymphatic absorption, with limited extravascular distribution, and minor contributions of the target-mediated drug disposition to the overall elimination are the common characteristics across the marketed ESA. Additionally, we assess the similarities and differences of ESAs related to pharmacodynamics in the context of the different biomarkers used to monitor the magnitude and duration of the effect, and introduce the concept of the minimum effective concentration of the ESA. The relationship between the minimum effective concentration and the half-life suggests that the time during which drug concentrations are above the minimum effective concentration is the main determinant of ESA efficacy in increasing Hb levels. The tolerance phenomenon and its physiological mechanism and implications for ESA dosing are discussed. Finally, the areas of future clinical pharmacology research are envisioned.Clinical Pharmacokinetics 08/2013; · 5.49 Impact Factor