Development and evaluation of a population pharmacokinetic (PK) model for darbepoetin alfa in healthy subjects

Abstract

Aims Darbepoetin alfa (DA) is a novel erythropoiesis stimulating protein with longer half-life, which allows for less frequent dosing. DA is approved for treatment of anemia associated with chemotherapy and chronic kidney disease. We describe the development and evaluation of a population PK model of DA in healthy subjects. Methods Serum DA concentration data were gathered from 50 healthy subjects (age 53–88 years) after intravenous and/or subcutaneous doses ranging from 0.75 to 9 μg/kg. Intensive PK profiles were obtained after single doses in all subjects. Results A population PK model, including first order absorption, two-compartment disposition, and first order elimination, provided adequate description of data. The drug exhibited flip-flop kinetics after SC administration. The influence of baseline covariates such as age, body weight, height, baseline hemoglobin, and gender on the model parameters was evaluated to obtain the final model, which was tested with posterior predictive and bootstrap tests. Simulations were performed using the final model to compare the PK after fixed versus weight-based DA dosing. Conclusions A population PK model which describes the inter-individual and intra-individual variability in DA PK and PK parameter-baseline covariate relationships was developed using robust modeling methodologies. The model is being used to predict PKPD response of DA in various therapeutic settings. Clinical Pharmacology & Therapeutics (2005) 77, P76–P76; doi: 10.1016/j.clpt.2004.12.182