A Differential Pharmacokinetic Analysis of the Erythropoietin Receptor Population in Newborn and Adult Sheep

Veng‐Pedersen, Peter; Chapel, Sunny; Al‐Huniti, Nidal; Schmidt, Robert L.; Sedars, E.M.; Hohl, R. J.; Widness, John A.

doi:10.1124/jpet.103.052431

Cited by 11 publications

(33 citation statements)

References 23 publications

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“…1, rate parameter K 1 ). This proposed elimination kinetics is consistent with our previous finding (Veng-Pedersen et al, 2003) that EPO is eliminated nonlinearly via a saturable erythropoietic mechanism and linearly via an apparent nonerythropoietic mechanism. The distribution effect in the PK model is represented by a distribution function (G⅐e Ϫ␥t ) according to disposition decomposition analysis principles (Veng-Pedersen, 1984).…”

Section: Methodssupporting

confidence: 92%

“…An increasing amount of evidence suggests that the metabolic fate of EPO is largely depending on EPO receptor (EPOR) carrying progenitor cells primarily located in the bone marrow that eliminate EPO through endocytosis of the EPOR-EPO complex followed by lysosomal degradation (Sawyer and Hankins, 1993). Ablation of the bone marrow changes the elimination kinetics from nonlinear (linear ϩ nonlinear) to purely linear, which supports the hypothesis that the nonlinear elimination kinetics is due to elimination via the EPOR pool located in the bone marrow (Veng-Pedersen et al, 2003). The present model provides further evidence to that hypothesis and estimates the Michaelis-Menten parameters (Fig.…”

Section: Discussionsupporting

confidence: 85%

“…The pharmacokinetics analysis of EPO plasma concentration profile from a single intravenous 125 I-rhEPO bolus dose was well described by a biexponential disposition function in agreement with our previous findings (Chapel et al, 2001;Veng-Pedersen et al, 2003). The clearances, including various PK parameters, were calculated from the biexponential disposition function using the computer program PERDIS (Veng-Pedersen and Gillespie, 1987).…”

Section: Methodssupporting

confidence: 85%

“…The mean value for the nonhematopoietic receptors, K 1 , estimated in this work was 0.176 Ϯ 55.1 h Ϫ1 (Table 1), which is comparable and not statistically different (p ϭ 0.21) to the estimate 0.128 Ϯ 17.9 h Ϫ1 from our previous work in adult sheep (Veng-Pedersen et al, 2003).…”

Section: Discussionsupporting

confidence: 75%

“…It is well recognized that EPOR exist in many tissues other than bone marrow (Yasada et al, 1993;Yamaji et al, 1996;Juul et al, 1998Juul et al, , 2001Nagai et al, 2001). The first-order elimination rate constant, K 1 , accounts for the linear elimination taking place outside the bone marrow (Veng-Pedersen et al, 2003). The role of these nonhematopoietic receptors is not well understood.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetic/Pharmacodynamic Analysis of Paradoxal Regulation of Erythropoietin Production in Acute Anemia

Al‐Huniti¹,

Widness²,

Schmidt³

et al. 2004

J Pharmacol Exp Ther

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The regulatory mechanism responsible for a paradoxal, rapid drop in the erythropoietin (EPO) plasma level seen 2 to 4 days after acute, phlebotomy-induced anemia was investigated in seven adult sheep. To introduce acute anemia, each sheep underwent two phlebotomies where the hemoglobin (Hb) was reduced to 3 or 4 g/dl over 4 to 5 h. The phlebotomies were spaced 4 to 6 weeks apart in three animals, and 8 days apart in four other animals. EPO plasma levels, reticulocyte count, Hb, and p50 for oxygen-Hb dissociation were determined from frequent blood samplings throughout the study period. EPO's disposition pharmacokinetic (PK) and plasma clearance were determined from i.v. bolus injections of tracer amounts of a recombinant human EPO tracer. The controlled drop in Hb resulted in a rapid increase in plasma EPO to 836 Ϯ 52 mU/ml (mean Ϯ coefficient of variation percentage) that was followed by a paradoxical rapid drop 2 to 4 days after the phlebotomy while the animals were still very anemic (Hb ϭ 4.3 Ϯ 15 g/dl). The rapid drop in plasma EPO level could not be explained by the up-regulated clearance (clearance increased by a factor of less than 2.5) or by physiological adaptation (no change in p50, p Ͼ 0.05, second phlebotomy to Hb ϭ 3g/dl inadequately stimulated the EPO production). The PK/pharmacodynamic (PD) analysis supports the hypothesis of a limited sustained high EPO production rate in acute anemia, which indicates an apparent deficiency in the regulation of EPO production in acute anemia. The hypothesis was supported by a PK/PD feedback inhibition model that showed good agreement with the data (r ϭ 0.973 Ϯ 1.57).Erythropoietin (EPO) is a 34-kDa glycoprotein that is the primary hormone regulator of erythrocyte production. The main objectives of the present study are to elucidate quantitatively the kinetic regulatory mechanisms responsible for the rapid drop in EPO plasma level seen 2 to 4 days after phlebotomy-induced acute anemia while the Hb is still very low and to identify kinetic parameters of importance in EPO's production to provide a scientific basis for optimal use of EPO. Addressing these two objectives will provide a better understanding of the many factors affecting the erythropoiesis that should lead to more effective clinical use of EPO. Previously, we published a PK/PD analysis that simultaneously linked EPO plasma level, reticulocyte, and Hb responses (Veng-Pedersen et al., 2002). However, a PK/PD analysis of the physiology of EPO production under induced phlebotomy anemia has not been reported. Therefore, this work extends our previous work by kinetically analyzing the next step in the erythropoiesis, namely, EPO production and its regulation.This physiology-oriented analysis is done through a comprehensive, integrated PK/PD analysis, which simultaneously quantitatively links the Hb concentration, EPO production, and plasma level responses. Of particular interest of the proposed kinetic model is its ability to estimate a number of physiologically important parameters and to provide a k...

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Section: Methodssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 85%

Section: Methodssupporting

confidence: 85%

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacokinetic/Pharmacodynamic Analysis of Paradoxal Regulation of Erythropoietin Production in Acute Anemia

Al‐Huniti¹,

Widness²,

Schmidt³

et al. 2004

J Pharmacol Exp Ther

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Preclinical Pharmacokinetics

Mager

Ramanathan

2010

Pharmaceutical Sciences Encyclopedia

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The preclinical pharmacokinetics of protein pharmaceuticals is distinctively different from small‐molecule drugs. Understanding the mechanisms and implications of in vivo disposition of macromolecules provides a means for investigating and designing novel drug candidates and delivery systems to optimize exposure‐response relationships or therapeutic efficacy. This article focuses on the different aspects of preclinical pharmacokinetics of protein pharmaceuticals.

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