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J Pharm Sci. 2017 Jun;106(6):1644-1649. doi: 10.1016/j.xphs.2017.02.001. Epub 2017 Feb 9.

Population Pharmacokinetics of Darbepoetin in Infants Following Single Intravenous and Subcutaneous Dosing.

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Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242. Electronic address:
Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico 87131.
Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132.
Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
Departments of Biochemistry and Molecular Biology and Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205.
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242.


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.


clinical pharmacokinetics; clinical trials; pharmacokinetic/pharmacodynamic models; pharmacokinetics; population pharmacokinetics

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