Receptor-based model accounts for phlebotomy-induced changes in erythropoietin pharmacokinetics

Chapel, Sunny; Veng‐Pedersen, Peter; Schmidt, Robert L.; Widness, John A.

doi:10.1016/s0301-472x(01)00614-2

Cited by 39 publications

(60 citation statements)

References 38 publications

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“…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%

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: 85%

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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“…Modeling for the CL R is similar to our group's previous work (Chapel et al, 2001) in that the feedback mechanism for the CL R is modeled through the use of an intermediate variable denoted M. The intermediate variable in this model provides a mathematical method to account for the clearance rebounding above the baseline value. A representative fitted Hb profile with the Epo concentrations is illustrated in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, the model assumes that Hb is produced only after the binding of Epo to its receptor, EpoR. It was also assumed that the receptor-based clearance of Epo (CL R ) is proportional to the EpoR pool size (Chapel et al, 2001). Finally, it was assumed that before the start of the study the system was at steady state; i.e., the Hb production was initially equal to the Hb removal resulting from red blood cell (RBC) senescence.…”

Section: Methodsmentioning

confidence: 99%

“…Several preclinical and clinical studies have reported an increase in Epo clearance within 1 month after Epo treatment (Kinoshita et al, 1992;Ohls et al, 1996;Widness et al, 1996;Sans et al, 2000), whereas others found no statistical difference (Salmonson et al, 1990;Kampf et al, 1992). An additional study modeled the change in the EpoR level over time after the induction of anemia (Chapel et al, 2001). In a recent study by our group, we reported up-regulation of EpoR mRNA levels of 4.97 Ϯ 3.92 times baseline at 9 days after the induction of anemia (Nalbant et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Receptor-Based Dosing Optimization of Erythropoietin in Juvenile Sheep after Phlebotomy

Rosebraugh

Widness²,

Veng‐Pedersen³

2011

Drug Metab Dispos

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“…Protein clearance by receptormediated endocytosis has been demonstrated for a number of proteins that exhibit nonlinear plasma kinetics, including erythropoietin (Chapel et al, 2001), granulocyte colony stimulating factor (Terashi et al, 1999), and hepatocyte growth factor (Liu et al, 1995). Additional mechanisms such as nonspecific renal and hepatic elimination processes and proteolytic degradation may also contribute to the removal of cytokines from the systemic circulation (Ferraiolo et al, 1992).…”

mentioning

confidence: 99%

Pharmacokinetics of Recombinant Human Leukemia Inhibitory Factor in Sheep

Segrave

Mager

Charman

et al. 2004

J Pharmacol Exp Ther

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The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 g/kg rhLIF (n ϭ 2) or s.c. doses of 10, 20, or 50 g/kg rhLIF (n ϭ 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Noncompartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF. The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration.

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Receptor-based model accounts for phlebotomy-induced changes in erythropoietin pharmacokinetics

Cited by 39 publications

References 38 publications

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

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

Receptor-Based Dosing Optimization of Erythropoietin in Juvenile Sheep after Phlebotomy

Pharmacokinetics of Recombinant Human Leukemia Inhibitory Factor in Sheep

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