Skip to main content
SpringerLink
Log in

Population Pharmacokinetics Meta-Analysis of Recombinant Human Erythropoietin in Healthy Subjects

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Objective

The aim of this analysis was to develop a population pharmacokinetic model to describe the pharmacokinetics of recombinant human erythropoietin (rHuEPO) in healthy subjects, after intravenous and subcutaneous administration over a wide dose range, and to examine the influence of demographic characteristics and other covariates on the pharmacokinetic parameters of rHuEPO.

Methods

Erythropoietin serum concentration data were available from 16 studies comprising 49 healthy subjects who received rHuEPO intravenous doses from 10 to 300 IU/kg, 427 healthy subjects who received rHuEPO subcutaneous doses from 1 to 2400 IU/kg, and 57 healthy subjects who received placebo and where endogenous erythropoietin concentrations were measured. Different pharmacokinetic models were fitted to the dataset using nonlinear mixed-effects modeling software (NONMEM, Version V, Level 1). Several patient covariates were tested in order to quantify the effect on rHuEPO pharmacokinetic parameters. Model evaluation was examined using a posterior predictive check.

Results

Erythropoietin showed a diurnal baseline variation of ±20%, described with a dual cosine model. Disposition was described with a two-compartment model with a small volume of distribution (6L) and parallel linear and nonlinear clearance. Total clearance varied between 0.3 and 0.9 L/h over the concentration range studied. A dual absorption model was used to characterise the rHuEPO absorption from the subcutaneous formulation and consisted of a faster pathway described as a sequential zero- and first-order absorption process and a parallel slower pathway characterised as a zero-order process. The bioavailability of subcutaneous rHuEPO increased from 30% at low doses to 71% at the highest dose of 160 kIU and was described using a hyperbolic model. The most important covariate effects were a decrease in the first-order absorption rate constant (ka) with increasing age, an increase in subcutaneous bioavailability with increasing baseline haemoglobin, and a decrease in bioavailability with increasing bodyweight. A posterior predictive check showed no systematic deviation of the simulated data from the observed values.

Conclusion

The population pharmacokinetic model developed is suitable to describe the pharmacokinetic behaviour of rHuEPO after intravenous and subcutaneous administration in healthy subjects, over a wide dose range.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Table I
Fig. 1
Fig. 2
Fig. 3
Table II
Fig. 4
Table III
Table IV
Fig. 5
Fig. 6

Similar content being viewed by others

Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Egrie JC, Strickland TW, Lane J, et al. Characterization and biological effects of recombinant human erythropoietin. Immunobiology 1986; 72: 213–24

    Article  Google Scholar 

  2. Wide L, Bengtsson C, Birgegard G. Circadian rhythm of erythropoietin in human serum. Br J Haematol 1989 May; 72(1): 85–90

    Article  PubMed  CAS  Google Scholar 

  3. Flaharty KK, Caro J, Erslev A, et al. Pharmacokinetics and erythropoietic response to human recombinant erythropoietin in healthy men. Clin Pharmacol Ther 1990 May; 47(5): 557–64

    Article  PubMed  Google Scholar 

  4. Salmonson T, Danielson BG, Wikstrom B. The pharmacokinetics of recombinant human erythropoietin after intravenous and subcutaneous administration to healthy subjects. Br J Clin Pharmacol 1990 Jun; 29(6): 709–13

    Article  PubMed  CAS  Google Scholar 

  5. McMahon FG, Vargas R, Ryan M, et al. Pharmacokinetics and effects of recombinant human erythropoietin after intravenous and subcutaneous injections in healthy volunteers. Blood 1990 Nov 1; 76(9): 1718–22

    PubMed  CAS  Google Scholar 

  6. Cheung WK, Goon BL, Guilfoyle MC, et al. Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects. Clin Pharmacol Ther 1998 Oct; 64(4): 412–23

    Article  PubMed  CAS  Google Scholar 

  7. Cheung WK, Minton N, Gunawardena K. Pharmacokinetics and pharmacodynamics of epoetin alfa once weekly and three times weekly. Eur J Clin Pharmacol 2001 Aug; 57(5): 411–8

    Article  PubMed  CAS  Google Scholar 

  8. Ramakrishnan R, Cheung WK, Wacholtz MC, et al. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers. J Clin Pharmacol 2004 Sep; 44(9): 991–1002

    Article  PubMed  CAS  Google Scholar 

  9. Toldman E. A double-blind, placebo controlled study of the safety and hematologic effects of single doses of recombinant-human erythropoietin in normal volunteers. Protocol F85-117. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 1987. (Data on file)

    Google Scholar 

  10. Toldman E. A double-blind evaluation of the safety and efficacy of multiple doses of erythropoietin (10 U/kg and 20 U/kg) and placebo in normal volunteers. Protocol F85-118. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 1988. (Data on file)

    Google Scholar 

  11. Toldman E. A double-blind evaluation of the safety and efficacy of multiple doses of recombinant human erythropoietin (100 U/kg, 200 U/kg, 300 U/kg) and placebo in normal volunteers. Protocol G86-047. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 1988. (Data on file)

    Google Scholar 

  12. Hutman HW, Fuentes E, Stevens DD. Pharmacokinetic and pharmacodynamic study comparing the standard cancer regimen of epoetin alfa to a weekly fixed dose regimen of epoetin alfa in healthy subjects. Protocol PRI/EPO-PHI-370. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 2001. (Data on file)

    Google Scholar 

  13. Riddell, JG. An open-label, randomized, two-period study to compare the pharmacokinetics, tolerance, and safety of subcutaneously administered doses of two formulations of epoetin alfa in normal male volunteers. Protocol EPO-PHI-352. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 1994. (Data on file)

    Google Scholar 

  14. Cheung WC, Nayak RK, Stubbs RJ, et al. An open-label, randomized, two-period crossover study to compare the safety and pharmacokinetics of subcutaneously administered single doses of epoetin alfa with and without a preservative in healthy male volunteers. Protocol EPO-PHI-353. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 1996. (Data on file)

    Google Scholar 

  15. Riddell JG. An open-label, randomized, two-period crossover study to compare the pharmacokinetics, tolerance, and safety of subcutaneously administered single 150 IU/kg doses of two formulations of epoetin alfa in normal male volunteers. Protocol EPO-PHI-354. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 1996. (Data on file)

    Google Scholar 

  16. Cheung WC. A double-blind, randomized, two-period crossover study to compare the pharmacokinetics, tolerance, and safety of subcutaneously administered single 150 IU/kg doses of two formulations of epoetin alfa in healthy male volunteers. Protocol EPO-INT-23/PHI-355. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 1997. (Data on file)

    Google Scholar 

  17. Wemer J. A double-blind, randomized, two-period crossover study to compare the pharmacokinetics, tolerance, and safety of subcutaneously administered single 750 IU/kg doses of two formulations of epoetin alfa in healthy male volunteers. Protocol EPO-INT-24/PHI-356. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 1997. (Data on file)

    Google Scholar 

  18. Bell D. pharmacokinetic and pharmacodynamic study comparing epoetin alfa 40,000 IU per week to 80,000 IU and 120,000 IU every two weeks in healthy male and female subjects. Protocol PRI/EPO-PHI-372. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 2002. (Data on file)

  19. Gunawardena KA. Pharmacokinetic and pharmacodynamic study comparing epoetin alfa 40,000 IU per week to 80,000 IU, 100,000 IU, and 120,000 IU every two weeks in healthy subjects. Protocol PRI/EPO-PHI-374. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 2001. (Data on file)

    Google Scholar 

  20. Ratnasingam L. An open-label, randomized, parallel-design study to investigate the pharmacokinetic and pharmacodynamic profiles of single subcutaneously administered doses of epoetin alfa in healthy male volunteers. Protocol EPO-PHI-380. Raritan (NJ): Johnson & Johnson Pharmaceutical Research and Development, 2001. (Data on file)

    Google Scholar 

  21. Guidance for Industry: Population Pharmacokinetics, US Food and Drug Administration, February 1999

  22. Beal SL, Sheiner LB. NONMEM users guides. San Francisco (CA): NONMEM Project Group, University of California at San Francisco, 1998

    Google Scholar 

  23. S-PLUS® 6.0. Modern statistics and advanced graphics. Seattle (WA): MathSoft, 2002

  24. Jonsson EN, Karlsson MO. Xpose: an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 1999; 58: 51–64

    Article  PubMed  CAS  Google Scholar 

  25. Wahlby U, Johnsson EN, Karlsson MO. Assessment of significance levels for covariate effects in NONMEM. J Pharmacokinet Pharmacodyn 2001; 28(3): 231–52

    Article  PubMed  CAS  Google Scholar 

  26. Gelman A, Carlin JB, Stern HS, et al. Bayesian data analysis. London: Chapman & Hall, 1995

    Google Scholar 

  27. Hayashi N, Kinoshita H, Yukawa E, et al. Pharmacokinetic analysis of subcutaneous erythropoietin administration with nonlinear mixed effect model including endogenous production. Br J Clin Pharmacol. 1998 Jul; 46(1): 11–9

    Article  PubMed  CAS  Google Scholar 

  28. Erslev AJ. In vitro production of erythropoietin by kidneys perfused with a serum-free solution. Blood 1974; 44: 77–85

    PubMed  CAS  Google Scholar 

  29. Koopman MG, Koomen GC, Krediet RT, et al. Circadian rhythm of glomerular filtration rate in normal individuals. Clin Sci 1989; 77: 105–11

    PubMed  CAS  Google Scholar 

  30. Stockmann C, Fandrey J. Hypoxia-induced erythropoietin production: a paradigm for oxygen-regulated gene expression. Clin Exp Pharmacol Physiol 2006 Oct; 33(10): 968–79

    Article  PubMed  CAS  Google Scholar 

  31. McLennan DN, Porter CJ, Edwards GA, et al. Lymphatic absorption is the primary contributor to the systemic availability of epoetin alfa following subcutaneous administration to sheep. J Pharmacol Exp Ther 2005 Apr; 313(1): 345–51

    Article  PubMed  CAS  Google Scholar 

  32. Agoram B, Sutjandra L, Sullivan JT. Population pharmacokinetics of darbepoetin alfa in healthy subjects. Br J Clin Pharmacol 2007; 63(1): 41–52

    Article  PubMed  CAS  Google Scholar 

  33. Porter CJ, Charman SA. Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci 2000; 89: 297–310

    Article  PubMed  CAS  Google Scholar 

  34. Veng-Pedersen P, Widness JA, Pereira LM, et al. Kinetic evaluation of nonlinear drug elimination by a disposition decomposition analysis: application to the analysis of the nonlinear elimination kinetics of erythropoietin in adult humans. J Pharm Sci 1995 Jun; 84(6): 760–7

    Article  PubMed  CAS  Google Scholar 

  35. Veng-Pedersen P, Widness JA, Pereira LM, et al. A comparison of nonlinear pharmacokinetics of erythropoietin in sheep and humans. Biopharm Drug Dispos 1999 May; 20(4): 217–23

    Article  PubMed  CAS  Google Scholar 

  36. Kato M, Kamiyama H, Okazaki A, et al. Mechanism for the nonlinear pharmacokinetics of erythropoietin in rats. J Pharmacol Exp Ther 1997 Nov; 283(2): 520–7

    PubMed  CAS  Google Scholar 

  37. Ramakrishnan R, Cheung WK, Farrell F, et al. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after intravenous and subcutaneous dose administration in cynomolgus monkeys. J Pharmacol Exp Ther 2003 Jul; 306(1): 324–31

    Article  PubMed  CAS  Google Scholar 

  38. Veng-Pedersen P, Chapel S, Al-Huniti NH, et al. Pharmacokinetic tracer kinetics analysis of changes in erythropoietin receptor population in phlebotomy-induced anemia and bone marrow ablation. Biopharm Drug Dispos 2004 May; 25(4): 149–56

    Article  PubMed  CAS  Google Scholar 

  39. Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn 2001 Dec; 28(6): 507–32

    Article  PubMed  CAS  Google Scholar 

  40. Piroso E, Erslev AJ, Caro J. Inappropriate increase in erythropoietin titers during chemotherapy. Am J Hematol 1999; 32: 248–54

    Article  Google Scholar 

  41. Jelkmann W. The enigma of the metabolic fate of circulating erythropoietin (Epo) in view of the pharmacokinetics of rhEpo and NESP. Eur J Hematol 2002; 69: 265–74

    Article  CAS  Google Scholar 

  42. Chapel S, Veng-Pedersen P, Hohl RJ, et al. Changes in erythropoietin pharmacokinetics following busulfan-induced bone marrow ablation: evidence for bone marrow as major erythropoietin elimination pathway. J Pharmacol Exp Ther 2001; 298: 820–4

    PubMed  CAS  Google Scholar 

  43. Mager DE. Target-mediated drug disposition and dynamics. Biochem Pharmacol 2006 Jun 28; 72(1): 1–10

    Article  PubMed  CAS  Google Scholar 

  44. Heatherington AC, Dittrich C, Sullivan JT, et al. Pharmacokinetics of darbepoetin alfa after intravenous or subcutaneous administration in patients with non-myeloid malignancies undergoing chemotherapy. Clin Pharmacokinet 2006; 45: 199–211

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Part of the content of this manuscript was presented as a poster (Olsson-Gislekog P, Jacqmin P, Perez-Ruixo JJ. Population pharmacokinetics of rHuEpo in healthy volunteers) at the XIV Meeting of the Population Approach Group in Europe (http://www.page-meeting.org/) in Pamplona, Spain, in June 2005.

The authors would like to thank Vladimir Piotrovsky, Andrew Chow and especially Wing Cheung for the comments and suggestions provided during the completion of this analysis. Juan Jose Perez Ruixo is an employee at Johnson & Johnson Pharmaceutical Research & Development, and Per Olsson-Gileskog and Philippe Jacqmin received consultation fees from Johnson & Johnson Pharmaceutical Research & Development. This study was supported by Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica, N.V., Beerse, Belgium.

Author information

Authors and Affiliations

  1. Exprimo Consulting, London, UK

    Per Olsson-Gisleskog & Philippe Jacqmin

  2. Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica N.V., Clinical Pharmacology, Turnhoutseweg 30, B-2340, Belgium

    Juan Jose Perez-Ruixo

Authors
  1. Per Olsson-Gisleskog
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philippe Jacqmin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juan Jose Perez-Ruixo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan Jose Perez-Ruixo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Olsson-Gisleskog, P., Jacqmin, P. & Perez-Ruixo, J.J. Population Pharmacokinetics Meta-Analysis of Recombinant Human Erythropoietin in Healthy Subjects. Clin Pharmacokinet 46, 159–173 (2007). https://doi.org/10.2165/00003088-200746020-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200746020-00004

Keywords

Search

Navigation