Darbepoetin alfa (Darbe) is a hyperglycosylated analogue of recombinant human erythropoietin (Epo). The aim of this study was to develop a population pharmacokinetic model for Darbe following intravenous (i.v.) and subcutaneous (s.c.) administration to infants. Data from 2 infant clinical studies (a single i.v. dose study following a 4 μg/kg dose of Darbe, and a single s.c. dose study following 1 μg/kg or 4 μg/kg dose of Darbe) were combined and analyzed simultaneously using nonlinear mixed-effect modeling approach. Darbe population pharmacokinetics was well described by a 2-compartment model with first-order elimination. The covariate analysis identified significant impact of gender on clearance and bodyweight on volume of distribution. The clearance of Darbe was estimated to be 0.050 L/h/kg in male infants and 0.031 L/h/kg in female infants. The predicted population mean value of Vp is 0.84 L/kg, which is associated with the subject's bodyweight (p < 0.05). Following s.c. administration, the estimated absorption rate (i.e., ka) of Darbe was 0.062 L/h. The model provides a suitable starting point for the development of further pharmacokinetic-pharmacodynamic models in infants in a variety of disease settings. Because the covariate-pharmacokinetic parameter relationships were identified in only 22 infants, further investigation with larger sample size is warranted.
Keywords: clinical pharmacokinetics; clinical trials; pharmacokinetic/pharmacodynamic models; pharmacokinetics; population pharmacokinetics.
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