Pharmacokinetic-Pharmacodynamic Modelling of Recombinant Human
			 Erythropoietin in Athletes

Varlet‐Marie, Emmanuelle; Gaudard, A.; Audran, Michel; Goméni, Roberto; Bressolle, Françoise

doi:10.1055/s-2003-39506

Cited by 15 publications

(8 citation statements)

References 17 publications

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“…The frequency of rhEPO administered to horses in this study was below that required to enhance athletic performance in humans (4,32). Daily administration of 50 U/kg to human athletes was required to increase reticulocytes on day 5 and hemoglobin on day 11 (32). To treat the EPO deficiency of chronic renal failure in humans, ϳ100 U⅐kg Ϫ1 ⅐wk Ϫ1 of rhEPO were administered (1).…”

Section: Discussionmentioning

confidence: 99%

Reticulocyte changes after experimental anemia and erythropoietin treatment of horses

Cooper¹,

Sears²,

Bienzle³

2005

Journal of Applied Physiology

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Availability of recombinant human erythropoietin (EPO) has facilitated use to enhance red blood cell production, and therefore aerobic performance, in human and equine athletes. Recombinant human EPO promotes growth and differentiation of equine erythroid precursor cells, but in some horses repeat administration induces immune interference with endogenous EPO resulting in fatal anemia. Although blood reticulocyte parameters acquire unique changes in humans treated with EPO, with manual enumeration methods, horses were not considered to release reticulocytes from the bone marrow into circulation, even under severe erythropoietic stress. The goals of this study were to determine whether reticulocytes could be detected and characterized in horses that are anemic or have been treated with EPO using a modern hematology analyzer. Anemia was induced in six horses by removal of 30 ml of blood/kg of body wt over 24 h. After 28 days, the horses were treated twice with 55 U/kg of EPO (Eprex), and after 65 days they were treated thrice with 73 U/kg of EPO. Blood samples were analyzed with the ADVIA120 instrument every 3-5 days and bone marrow samples 7 days after anemia and EPO treatments. Analysis of blood reticulocyte parameters by ANOVA in a randomized complete block design determined that anemia and EPO induced significant (P < or = 0.05) increases in red cell distribution width and reticulocyte mean cell volume. Parameters changed only after EPO treatment were cellular hemoglobin concentration mean, mean cell volume, reticulocyte concentration, proportion of macrocytic reticulocytes, and reticulocyte cellular hemoglobin. These findings indicate that horses under erythropoietic stress and after EPO treatment release reticulocytes with unique characteristics into circulation.

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Section: Discussionmentioning

confidence: 99%

Reticulocyte changes after experimental anemia and erythropoietin treatment of horses

Cooper¹,

Sears²,

Bienzle³

2005

Journal of Applied Physiology

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“…As depicted in Figure 1A, the boosting period was followed by a 10-day period without injections to allow total washout of rhEPO. [10] At 9 p.m. subjects received an intravenous micro-dose injection of approximately 900 IU epoietin alpha (Eprex®, Janssen, Birkerod, Denmark) representing about 11 IU/kg bodyweight. In the second protocol, the intravenous micro-dose was either 500 IU or 900 IU epoietin alpha representing about 6.5 IU/kg and 11 IU/kg bodyweight respectively ( Figure 1B).…”

Section: Methodsmentioning

confidence: 99%

New insights for identification of doping with recombinant human erythropoietin micro‐doses after high hydration

Martin

Ashenden²,

Bejder

et al. 2016

Drug Testing and Analysis

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To minimize the chances of being caught after doping with recombinant human erythropoietins (rhEPO), athletes have turned to new practices using micro-doses and excess fluid ingestion to accelerate elimination and decrease the probability of detection. Our objective was to test the sensitivity of detection by validated methods (IEF: isoelectric focusing; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis) when such practices are used. First, after a three-week rhEPO boost period and 10 days of wash out, detection of a single 900 IU micro-dose of Eprex® was evaluated in healthy male subjects. After an injection in the evening, urine and plasma samples were collected the following morning. Half of the subjects then drank a bolus of water and new samples were collected 80 min later. Interestingly, rhEPO was detected in 100% of the samples even after water ingestion. A second similar protocol was then performed with a single injection of a micro-dose of rhEPO (500 IU or 900 IU), without a prior rhEPO boost. In addition, urine and plasma samples were also collected 15 and 20 h post rhEPO administration. Once again drinking water did not affect the rate of detection. Urine appeared a better matrix to detect micro-doses after 10 h, enabling between 92% and 100% of identification at that time. The rate of identification decreased rapidly thereafter, in particular for the 500 IU micro-dose. However IEF analysis still resulted in 71% identification of rhEPO in urine after 20 h. These results could help to define a better strategy for controlling and identifying athletes using rhEPO micro-doses. Copyright © 2016 John Wiley & Sons, Ltd.

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“…injection of recombinant human erythropoietin to athletes demonstrated a mean half-life of 35.5 h, which was four- to five-times longer (∼42 h) compared with iv. administration where half-life was 4–7 h, suggesting flip–flop pharmacokinetics [125]. Modeling of iv.…”

Section: Drug Examplesmentioning

confidence: 99%

Flip-flop Pharmacokinetics – Delivering a Reversal of Disposition: Challenges and Opportunities During Drug Development

Yáñez

Remsberg

Sayre

et al. 2011

Therapeutic Delivery

206

108

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Flip-flop pharmacokinetics is a phenomenon often encountered with extravascularly administered drugs. Occurrence of flip-flop spans preclinical to human studies. The purpose of this article is to analyze both the pharmacokinetic interpretation errors and opportunities underlying the presence of flip-flop pharmacokinetics during drug development. Flip-flop occurs when the rate of absorption is slower than the rate of elimination. If it is not recognized, it can create difficulties in the acquisition and interpretation of pharmacokinetic parameters. When flip-flop is expected or discovered, a longer duration of sampling may be necessary in order to avoid overestimation of fraction of dose absorbed. Common culprits of flip-flop disposition are modified dosage formulations; however, formulation characteristics such as the drug chemical entities themselves or the incorporated excipients can also cause the phenomenon. Yet another contributing factor is the physiological makeup of the extravascular site of administration. In this article, these causes of flip-flop pharmacokinetics are discussed with incorporation of relevant examples and the implications for drug development outlined.

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Pharmacokinetic-Pharmacodynamic Modelling of Recombinant Human Erythropoietin in Athletes

Cited by 15 publications

References 17 publications

Reticulocyte changes after experimental anemia and erythropoietin treatment of horses

Reticulocyte changes after experimental anemia and erythropoietin treatment of horses

New insights for identification of doping with recombinant human erythropoietin micro‐doses after high hydration

Flip-flop Pharmacokinetics – Delivering a Reversal of Disposition: Challenges and Opportunities During Drug Development

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