Recombinant Human Erythropoietin for the Treatment of Renal Anaemia in Children
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ORIGINAL RESEARCH ARTICLE
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Recombinant Human Erythropoietin for the Treatment of Renal Anaemia in Children No Justification for Bodyweight-Adjusted Dosage Ruediger E. Port,1 Daniela Kiepe,2 Michael Van Guilder,3 Roger W. Jelliffe3 and Otto Mehls2 1 2 3
German Cancer Research Center, Heidelberg, Germany Pediatric University Hospital, Heidelberg, Germany Laboratory of Applied Pharmacokinetics, Division of Geriatric Medicine, University of Southern California School of Medicine, Los Angeles, California, USA
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 (Emax) model with median Emax = 0.29 g/dL, median 50% effective dose (ED50) = 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 Emax and ED50 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 Emax, ED50 and τ.
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Long-term administration of recombinant human erythropoietin (epoetin), following the first clinical trials in the mid-1980s, has become the most common way of treating anaemia in end-stage renal disease.[1-3] Standard amounts per unit bodyweight have been recommended for the initial dose.[1,2] However, several authors have noted that the dose per unit bodyweight needed for a given response is higher in younger children than in older children or adolescents[4-6] and that it increases with decreasing b
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