PubMed · 12324929
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Allen R Nissenson. 2002. Dosing darbepoetin alfa.. https://doi.org/10.1053/ajkd.2002.36566
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AIM: To develop and evaluate a population pharmacokinetic (PK) model of the long-acting erythropoiesis-stimulating protein, darbepoetin alfa in healthy subjects. METHODS: PK profiles were obtained from 140 healthy subjects receiving single intravenous and/or single or multiple subcutaneous doses of darbepoetin alfa (0.75-8.0 microg kg(-1), or either 80 or 500 microg). Data were analysed by a nonlinear mixed-effects modelling approach using NONMEM software. Influential covariates were identified by covariate analysis emphasizing parameter estimates and their confidence intervals, rather than stepwise hypothesis testing. The model was evaluated by comparing simulated profiles (obtained using the covariate model) to the observed profiles in a test dataset. RESULTS: The population PK model, including first-order absorption, two-compartment disposition and first-order elimination, provided a good description of data. Modelling indicated that for a 70-kg human, the observed nearly twofold disproportionate dose-exposure relationship at the 8.0 microg kg(-1)-dose relative to the 0.75 microg kg(-1)-dose may reflect changing relative bioavailability, which increased from approximately 48% at 0.75 microg kg(-1) to 78% at 8.0 microg kg(-1). The covariate analysis showed that increasing body weight may be related to increasing clearance and central compartment volume, and that the absorption rate constant decreased with increasing age. The full covariate model performed adequately in a fixed-effects prediction test against an external dataset. CONCLUSION: The developed population PK model describes the inter- and intraindividual variability in darbepoetin alfa PK. The model is a suitable tool for predicting the PK response of darbepoetin alfa using clinically untested dosing regimens.
OBJECTIVE: Previous studies suggest that darbepoetin might stimulate erythropoiesis in preterm neonates more effectively if injected subcutaneously (s.c.) than if infused intravenously (i.v.). It has been postulated that this is because very high plasma concentrations after i.v. dosing result in urinary loss of the drug. However, this theory has not been tested systematically, and no direct comparisons have been made between s.c. and i.v. dosing of darbepoetin in preterm neonates. STUDY DESIGN: Preterm neonates were eligible for this pilot study if they were born at < or =32 weeks gestation with a weight of < or =1500 g, and had a hemoglobin < or =10.5 g/dl. The darbepoetin was given (4 microg/kg) i.v., over 4 h, if an i.v. was already in place and s.c. if no i.v. was in place. Urine was collected for drug quantification before dosing and for 48 h after. Blood was obtained for immature reticulocyte fraction (IRF), absolute reticulocyte count (ARC) and reticulocyte % before and 96 h after dosing. RESULTS: Ten preterm neonates were studied: five received i.v. and five received s.c. darbepoetin. No adverse effects of the administrations were detected. IRF, ARC and reticulocyte % increased in the i.v. and s.c. recipients, and no difference in magnitude of increase was apparent between the groups. Before the darbepoetin was administered, none of the patients had any erythropoietin (Epo) detected in their urine. After i.v. dosing, no darbepoetin was detected in any of the samples, on any of the subjects, over the subsequent 48 h. After s.c. dosing, three of the patients had minimal urinary Epo detected. The patient with the largest urinary loss of drug had only 0.13% of the administered dose detected in the urine. Thus, essentially no urinary loss of drug was observed following either i.v. or s.c. darbepoetin dosing. CONCLUSION: Darbepoetin loss into the urine was below detectable limits among seven patients, while three had minimally detectable urinary losses. i.v. and s.c. dosing resulted in approximately equivalent increases in reticulocyte response when measured 96 h after dosing. On this basis, we speculate that if a patient who is to receive darbepoetin has an i.v. in place, the drug can be given i.v., thus avoiding any discomfort associated with an s.c. injection.
Drug testing is now ubiquitous in sport, and it often falls to the team physician to perform a variety of roles including interpreting test results, designing drug-testing programs, acting as medical review officer, and providing therapeutic use exemptions, education, and counseling. Proper understanding of current testing methods for drugs such as anabolic-androgenic steroids, erythropoietin, and growth hormone is essential if the team physician is going to assume these positions. This article outlines the basics of athletic drug testing from the collection process through the interpretation of results to assist the team physician in this field.