# Recombinant Human Erythropoietin for the Treatment of Renal Anaemia in Children

- 71 Downloads
- 18 Citations

## Abstract

**Background:** Drug doses for children are usually calculated by reducing adult doses in proportion to bodyweight. The clinically effective dose of recombinant human erythropoietin (epoetin) in children, however, seems to be higher than predicted by this calculation.

**Objective:** To determine the quantitative relationship between epoetin dose, bodyweight and response in children with end-stage renal disease.

**Patients and Methods:** The time-course of haemoglobin in 52 children during long-term treatment with epoetin beta was analysed by population pharmacodynamic modelling. Patients were 5–20 years old and weighed 16–53kg at the beginning of treatment. Epoetin beta was given intravenously three times per week after haemodialysis. Doses ranged from 110 to 7500IU (3–205 IU/kg). Haemoglobin versus time was described by assuming that the haemoglobin level rises after each dose due to the formation of new red blood cells, which then survive according to a logistic function. The initial rise after each dose was modelled in terms of absolute dose (not dose/kg). A parametric analysis was done with NONMEM, followed by a nonparametric analysis with NPAG.

**Results:** Dose-response was best described by a sigmoid maximum-effect (E_{max}) model with median E_{max} = 0.29 g/dL, median 50% effective dose (ED_{50}) = 2400IU and shape parameter γ = 2. The estimated median survival time of the epoetin-induced red blood cells, τ, was 76 days. Neither of the dose-response parameters E_{max} and ED_{50} showed dependence on bodyweight. The median haemoglobin response to a standard dose, 0.042 g/dL for 1000IU, was similar to that reported for adults with intravenous administration.

**Conclusions:** Doses for children in this age range should be specified as absolute amounts rather than amounts per unit bodyweight. Initial doses can be calculated individually, based on haemoglobin level before treatment, the desired haemoglobin at steady state and the median population parameters E_{max}, ED_{50} and τ.

## Keywords

Recombinant Human Erythropoietin Cystinosis Renal Anaemia Absolute Dose Constant Dose Rate## Notes

### Acknowledgements

Supported by the Deutsche Forschungsgemeinschaft, grant no. PO 482/2-1. The original data were kindly made available by Roche AG, Mannheim, Germany. We are grateful to Karl Schaerer and Sunny Hong Chapel for stimulating discussions. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

## References

- 1.Working Party for European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 1999; 14 Suppl. 5: 1–50Google Scholar
- 2.National Kidney Foundation. K/DOQI Clinical practice guidelines for anemia of chronic kidney disease, 2000. Am J Kidney Dis 2001; 37Suppl. 1: S182–238Google Scholar
- 3.Eckardt KU. Erythropoietin: Karriere eines Hormons. Dtsch Arztebl 1998; 95: A255–90Google Scholar
- 4.Scigalla P. Effect of recombinant human erythropoietin treatment on renal anemia and body growth of children with endstage renal disease. In: Baldamus CA, Scigalla P, Wieczorek L, et al, editors. Erythropoietin in renal and non-renal anemias. Basel: Karger, 1991Google Scholar
- 5.Gagnadoux MF, Loirat C, Bertheleme JP, et al. Treatment of anemia in hemodialyzed children using recombinant human erythropoietin (Eprex). Results of a French multicenter clinical trial [in French]. Nephrologie 1994; 15: 207–11PubMedGoogle Scholar
- 6.Jabs K, Alexander S, McCabe D. Primary results from the U.S. multicenter pediatric recombinant erythropoietin (epo) study [abstract]. J Am Soc Nephrol 1994; 5: 456Google Scholar
- 7.van Damme-Lombaerts R, Broyer M, Businger J, et al. A study of recombinant human erythropoietin in the treatment of anemia of chronic renal failure in children on haemodialysis. Pediatr Nephrol 1994; 8: 338–42PubMedCrossRefGoogle Scholar
- 8.van Damme-Lombaerts R, Herman J. Erythropoietin treatment in children with renal failure. Pediatr Nephrol 1999; 13: 148–52PubMedCrossRefGoogle Scholar
- 9.Uehlinger DE, Gotch FA. A pharmacodynamic model of erythropoietin therapy for uremic anemia [abstract]. J Am Soc Nephrol 1990; 1: 324Google Scholar
- 10.Uehlinger DE, Gotch FA, Sheiner LB. A pharmacodynamic model of erythropoietin therapy for uremic anemia. Clin Pharmacol Ther 1992; 51: 76–89PubMedCrossRefGoogle Scholar
- 11.Brockmoeller J, Koechling J, Weber W, et al. The pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in hemodialysis patients. Br J Clin Pharmacol 1992; 34: 499–508Google Scholar
- 12.Bellazzi R. Drug delivery optimization through Bayesian networks: an application to erythropoietin therapy in uremic anemia. Comput Biomed Res 1992; 26: 274–93CrossRefGoogle Scholar
- 13.Matzke GR, Comstock T, Frye RF, et al. Computerized Bayesian pharmacodynamic modeling for erythropoietin dosage individualization [abstract]. J Am Soc Nephrol 1994; 5: 464Google Scholar
- 14.Port RE, Ding RW, Fies T, et al. Predicting the time course of haemoglobin in children treated with erythropoietin for renal anaemia. Br J Clin Pharmacol 1998; 46: 461–6PubMedCrossRefGoogle Scholar
- 15.Scigalla P, Bonzel KE, Bulla M, et al. Therapy of renal anemia with recombinant human erythropoietin in children with endstage renal disease. In: Gurland HL, Moran J, Samtleben W, et al, editors. Erythropoietin: from molecular structure to clinical application. Basel: Karger, 1989Google Scholar
- 16.Eadie GS, Brown IW. Red blood cell survival studies. Blood 1953; 8: 1110–36PubMedGoogle Scholar
- 17.Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. 3rd ed. Baltimore (MD): Williams & Wilkins, 1995Google Scholar
- 18.Harris JW, Kellermeyer RW. The Red Cell. 2nd ed. Cambridge (MA): Harvard University Press, 1970Google Scholar
- 19.Sheiner LB, Ludden TM. Population pharmacokinetics/dynamics. Annu Rev Pharmacol Toxicol 1992; 32: 185–209PubMedCrossRefGoogle Scholar
- 20.Jelliffe R, Schumitzky A, van Guilder M. Population pharmacokinetics/pharmacodynamics modeling: parametric and nonparametric methods. Ther Drug Monit 2000; 22: 354–65PubMedCrossRefGoogle Scholar
- 21.Beal SL, Sheiner LB, editors. NONMEM version V.1.1, user’s guides. San Francisco (CA): NONMEM Project Group, University of California, San Francisco, 1999Google Scholar
- 22.Leary RH, Jelliffe RW, Schumitzky A, et al. Non-parametric pharmacokinetic/dynamic population modeling with adaptive grids [abstract]. Clin Pharmacol Ther 2001; 69: P58Google Scholar
- 23.MathSoft Inc. S-Plus, version 6.0, release 1 for Linux 2.2.12 or higher. Seattle (WA): MathSoft Inc., 2001Google Scholar
- 24.Sheiner LB, Rosenberg B, Marathe VV. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmacokinet Biopharm 1977; 5: 445–79PubMedGoogle Scholar
- 25.Sheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 1981; 9: 503–12PubMedGoogle Scholar
- 26.Kling PJ, Widness JA, Guillery EN, et al. Pharmacokinetics and pharmacodynamics of erythropoietin during therapy in an infant with renal failure. J Pediatr 1992; 121: 822–5PubMedCrossRefGoogle Scholar
- 27.Widness JA, Veng-Pedersen P, Modi NB, et al. Developmental differences in erythropoietin pharmacokinetics: increased clearance and distribution in fetal and neonatal sheep. J Pharmacol Exp Ther 1992; 261: 977–84PubMedGoogle Scholar
- 28.Widness JA, Veng-Pedersen P, Peters C, et al. Erythropoietin pharmacokinetics in premature infants: developmental, non-linearity, and treatment effects. J Appl Physiol 1996; 80: 140–8PubMedGoogle Scholar
- 29.Veng-Pedersen P, Widness JA, Pereira LM, et al. A comparison of nonlinear pharmacokinetics of erythropoietin in sheep and humans. Biopharm Drug Dispos 1999; 20: 217–23PubMedCrossRefGoogle Scholar
- 30.Chapel SH, Veng-Pedersen P, Schmidt RL, et al. Receptor-based model accounts for phlebotomy-induced changes in erythropoietin pharmacokinetics. Exp Hematol 2001; 29: 425–31PubMedCrossRefGoogle Scholar
- 31.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; 84: 760–7PubMedCrossRefGoogle Scholar
- 32.Veng-Pedersen P, Widness JA, Wang J, et al. A tracer interaction method for nonlinear pharmacokinetics analysis: application to evaluation of nonlinear elimination. J Pharmacokinet Biopharm 1997; 25: 569–93PubMedGoogle Scholar
- 33.Widness JA, Veng-Pedersen P, Schmidt RL, et al. In vivo
^{125}I-erythropoietin pharmacokinetics are unchanged after anesthesia, nephrectomy and hepatectomy in sheep. J Pharmacol Exp Ther 1996; 279: 1205–10PubMedGoogle Scholar - 34.Juul SE. Erythropoietin in the neonate. Curr Probl Pediatr 1999; 29(5): 133–49CrossRefGoogle Scholar
- 35.Juul SE. Nonerythropoietic roles of erythropoietin in the fetus and neonate. Clin Perinatol 2000; 27: 527–41PubMedCrossRefGoogle Scholar
- 36.Bommer J, Barth HP, Zeier M, et al. Efficacy comparison of intravenous and subcutaneous recombinant human erythropoietin administration in hemodialysis patients. Contrib Nephrol 1991; 88: 136–43PubMedGoogle Scholar
- 37.Jelliffe RW, Schumitzky A, Bayard D, et al. Model-based, goal-oriented, individualised drug therapy. linkage of population modelling, new ‘multiple model’ dosage design, Bayesian feedback and individualised target goals. Clin Pharmacokinet 1998; 34: 57–77PubMedCrossRefGoogle Scholar
- 38.Steimer JL, Mallet A, Mentre F. Estimating interindividual pharmacokinetic variability. In: Rowland M, Sheiner LB, Steimer JL, editors. Variability in drug therapy. New York: Raven Press, 1985: 65–111Google Scholar
- 39.Mallet A. A maximum likelihood estimation method for random coefficient regression models. Biometrika 1986; 73: 645–56CrossRefGoogle Scholar