Pharmacokinetic-Pharmacodynamic Modelling of Recombinant Human Erythropoietin in Athletes

Abstract

The aim of this study was to develop a pharmacokinetic model that takes into account the negative feedback loop of endogenous erythropoietin production observed after repeated recombinant human erythropoietin administration. A pharmacodynamic data analysis was performed using the changes in i) reticulocyte count, ii) serum levels of soluble transferrin receptors, and iii) soluble transferrin receptors/serum proteins ratio as an index of the therapeutic effect of the hormone. Nine athletes were included in the study; they received repeated subcutaneous administrations (50 IU × kg^-1per day) of recombinant human erythropoietin. The mean half-life of the terminal part of the curve was 35.5 h, and the total clearance was 17 ml × h^-1 × kg^-1. The total clearance was about two times higher in athletes than in untrained subjects (5.5 - 7.5 ml × h^-1 × kg^-1) and the half-life period of plasma erythropoietin after subcutaneous administration was five times longer compared to intravenous administration (4 to 7 h). Thus, after subcutaneous administration, the terminal part of the curve should correspond to the absorption phase, instead of to the elimination phase (flip-flop phenomenon). The pharmacodynamic relationship based on a sigmoid E _max model can be reasonably used to relate the changes observed in the markers to recombinant human erythropoietin administration. Recombinant human erythropoietin induces a delayed increase in reticulocytosis and in soluble transferrin receptor levels. In comparison with baseline, the increase of these markers became significant from the third and the tenth day after the initial administration of the hormone, respectively. These results were in accordance with the equilibration delay computed from the pharmacokinetic-pharmacodynamic data modelling (half-life of 25.7 h and 10 days, respectively). The recombinant hormone was well tolerated during this study.

Key words

Erythropoietin abuse - repeated subcutaneous administrations - negative feedback loop - indirect detection

References

• 1 Annable L, Cotes P M, Musset M V. The Second International Reference Preparation of Epo, human, urinary, for bioassay.  Bull Wld Hlth Org. 1972;  47 99-112
• 2 Audran M, Gareau R, Matecki S, Durand F, Chenard C, Sicart M T, Marion B, Bressolle F. Indirect detection of erythropoietin abuse in doping control.  Med Sci Sports Exerc. 1999;  31 639-653
• 3 Beal S L, Sheiner L B. NONMEM User’s Guide,. University of California at San Francisco San Francisco, USA:;
• 4 Berglund B, Ekblom B. Effect of recombinant human erythropoietin treatment on blood pressure and some haematological parameters in healthy males.  J Intern Med. 1991;  229 125-130
• 5 Birkeland K, Hemmersbach P. Issues related to blood sampling in athletes for doping control.  Sports Med. 1999;  28 25-30
• 6 Bressolle F, Audran M, Gareau R, Baynes R D, Guidicelli C, Gomeni R. Population pharmacodynamics for monitoring of recombinant human erythropoietin: a new approach in doping control.  Clin Drug Invest. 1997;  14 233-242
• 7 Casoni I, Ricci G, Ballarin E, Borseto C, Grazzi G, Guglielmini C, Manfredi F, Mazzoni G, Patracchini M, de Paoli Vitali E , Rigolin F, Bartalotta S, Franzè G P, Masotti M, Conconi F. Haematological indices of erythropoietin administration in athletes.  Int J Sports Med. 1993;  14 307-311
• 8 Cotes P M, Brozovic B. Diurnal variation of serum immunoreactive erythropoietin in a normal subject.  Clin Endocrinol. 1982;  17 419-422
• 9 Eckardt K U, Kurtz A, Hirth P, Scigalla P, Wieczorek L, Bauer C. Evaluation of the stability of human erythropoietin in samples for radioimmunoassay.  Klin Wschr. 1988;  66 241-245
• 10 Ekblom B, Berglund B. Effect of erythropoietin administration on maximal aerobic power in man.  Scand J Med Sci Sports. 1991;  1 88-93
• 11 Fuseau E, Sheiner L B. Simultaneous modeling of pharmacokinetics and pharmacodynamics with nonparametric pharmacodynamic model.  Clin Pharmacol Ther. 1984;  35 733-741
• 12 Gareau R, Gagnon M G, Ayotte C, Chenard C, Brisson G R. rHuEpo increases urinary excretion of fibrin degradation products in haemodialysis patients.  Thromb Haemost . 1993;  70 373-374
• 13 Gareau R, Gagnon M G, Thellend C, Chenard C, Audran M, Chanal J L, Ayotte C, Brisson G R. Transferrin soluble receptor: a possible probe for detection of erythropoietin abuse by athletes.  Horm Metab Res. 1994;  26 311-312
• 14 Halstenson C E, Macres M, Katz S A, Schnieders J R, Watanabe M, Sobota J T, Abraham P A. Comparative pharmacokinetics and pharmacodynamics of epoetin alpha and epoetin beta.  Clin Pharmacol Ther. 1991;  50 702-712
• 15 Jensen J D, Jensen L W, Madsen J K, Poulsen L. The metabolism of erythropoietin in liver cirrhosis patients compared with healthy volunteers.  Eur J Haematol. 995;  54 111-116
• 16 Jelkman W. Biology of erythropoietin.  Clin Invest. 1994;  72 S3-S10
• 17 Kicman A T, Cowan D A. Peptides hormones and sport: misuse and detection.  Br Med Bull. 1992;  48 496-517
• 18 Klausen T, Dela F, Hippe E, Galbo H. Diurnal variations of serum erythropoietin in trained and untrained subjects.  Eur J Appl Physiol. 1993;  67 545-548
• 19 Koury M J, Bondurant M C. The molecular mechanism of erythropoietin action.  Eur J Biochem. 1992;  210 649-663
• 20 Magnani M, Corsi D, Blanchi M, Palardini M, Galluzzi L, Parisi A, Pigozzi F. Monitoring erythropoietin abuse in athletes.  Br J Haematol. 1999;  106 260-261
• 21 McMahon F G, Vargas R, Ryan M, Jain A K, Abels R I, Peery B, Smith I L. Pharmacokinetics and effects of recombinant human erythropoietin after intravenous and subcutaneous injection in healthy volunteers.  Blood . 1990;  76 1718-1722
• 22 Miller M E, Garcia J F, Cohen R A, Cronkite E P, Moccia G, Jacevedo R. Diurnal levels of immunoreactive erythropoietin in normal subjects and subjects with chronic lung disease.  Br J Haematol. 1981;  49 189-200
• 23 Parisotto R, Gore C J, Emslie K R, Asheden M J, Brugnara C, Howe C, Martin T, Trout G T, Hahn A G. A novel method utilizing markers of altered erythropoiesis for the detection of recombinant human erythropoietin abuse in athletes.  Haematologica. 2000;  85 564-572
• 24 Parisotto R, Moutian W, Asheden M J, Emslie K R, Gore C J, Howe , C . Kazlauskas R, Sharpe K, Trout GJ, Xie M, Hahn AG. Detection of recombinant human erythropoietin abuse in athletes utilizing markers of altered erythropoiesis.  Haematologica. 2001;  86 128-137
• 25 Parisotto R. , Gore CJ, Hahn AG, Asheden MJ, Olds TS, Martin DT, Pyne DB, Gawthorn K, Brugnara C. Reticulocyte parameters as potential discriminators of recombinant human erythropoietin abuse in elite athletes.  Int J Sports Med. 2000;  21 471-479
• 26 Salmonson T, Danielson B G, Wikström B. The pharmacokinetics of recombinant erythropoietin after intravenous and subcutaneous administration to healthy subjects.  Br J Clin Pharmacol. 1990;  29 709-713
• 27 Sawka M N, Joyner M J, Miles D S, Robertson R J, Spriet L L, Young A J. The use of blood doping as an ergogenic aid.  Med Sci Sports Exerc. 1996;  28 I-VIII
• 28 Schwandt H J, Heyduck B, Genga H C, Rocker L. Influence of prolonged physical exercise on the erythropoietin concentration in blood.  Eur J Appl Physiol. 1991;  63 463-466
• 29 Schmidt W, Eckardt K U, Hilgendorf A, Strauch S, Bauer C. Effect of maximal and submaximal exercise under normoxic and hypoxic conditions on serum erythropoietin level.  Int J Sports Med. 1991;  12 457-461
• 30 Souillard A, Audran M, Bressolle F, Gareau R, Duvallet A, Chanal J L. Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in athletes. Blood sampling and doping control.  Br J Clin Pharmacol. 1996;  42 355-360
• 31 Veng-Pedersen P, Widness J A, Pereira L M, Peters C, Schmidt R L, Lowe L S. Kinetic evaluation of nonlinear drug elimination by a disposition decomposition analysis. Application to the analysis of the linear elimination kinetics of erythropoietin in adult humans.  J Pharm Sci. 1995;  84 760-767