title: Population Pharmacokinetics of Darbepoetin in Infants Following Single Intravenous and Subcutaneous Dosing.
abstract: 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.
authors.affiliation: Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242. Electronic address: Guohua-an@uiowa.edu.
authors.forename: Guohua
authors.initials: G
authors.lastname: An
authors.affiliation: Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico 87131.
authors.forename: Robin K
authors.initials: RK
authors.lastname: Ohls
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah 84132.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Christensen
authors.affiliation: Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
authors.forename: John A
authors.initials: JA
authors.lastname: Widness
authors.affiliation: Departments of Biochemistry and Molecular Biology and Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Mock
authors.affiliation: Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242.
authors.forename: Peter
authors.initials: P
authors.lastname: Veng-Pedersen
mesh_terms: D000279:Administration, Cutaneous; D061605:Administration, Intravenous; D002675:Child, Preschool; D000068256:Darbepoetin alfa / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006397:Hematinics / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological
chemical_list: D006397:Hematinics; D000068256:Darbepoetin alfa
keywords: clinical pharmacokinetics; clinical trials; pharmacokinetic/pharmacodynamic models; pharmacokinetics; population pharmacokinetics