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Population pharmacokinetics of darbepoetin alfa in healthy subjects
Author(s) -
Agoram Balaji,
Sutjandra Liviawati,
Sullivan John T.
Publication year - 2007
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2006.02752.x
Subject(s) - nonmem , covariate , pharmacokinetics , population , darbepoetin alfa , medicine , volume of distribution , bioavailability , confidence interval , pharmacology , statistics , mathematics , erythropoietin , environmental health
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 µg kg −1 , or either 80 or 500 µg). 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 µg kg −1 ‐dose relative to the 0.75 µg kg −1 ‐dose may reflect changing relative bioavailability, which increased from ∼ 48% at 0.75 µg kg −1 to 78% at 8.0 µg 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.