Recombinant human erythropoietin for the treatment of renal anaemia in children: no justification for bodyweight-adjusted dosage.
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.


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 gamma = 2. The estimated median survival time of the epoetin-induced red blood cells, tau, 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 tau.
Port
Ruediger E
RE
German Cancer Research Center, Heidelberg, Germany. r.port@dkfz.de
Kiepe
Daniela
D
Van Guilder
Michael
M
Jelliffe
Roger W
RW
Mehls
Otto
O
D000293:Adolescent; D000328:Adult; D000740:Anemia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage / Q000627:therapeutic use; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications* / Q000628:therapy; D008954:Models, Biological; D011994:Recombinant Proteins; D006435:Renal Dialysis; D018709:Statistics, Nonparametric
D006454:Hemoglobins; D011994:Recombinant Proteins; D004921:Erythropoietin