Population pharmacokinetics of darbepoetin alfa in healthy subjects

Abstract

AimTo develop and evaluate a population pharmacokinetic (PK) model of the long-acting erythropoiesis-stimulating protein, darbepoetin alfa in healthy subjects. MethodsPK profiles were obtained from 140 healthy subjects receiving single intravenous and/or single or multiple subcutaneous doses of darbepoetin alfa (0.75-8.0 µ g kg − 1 , or either 80 or 500 µ g). 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. ResultsThe 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 doseexposure relationship at the 8.0 µ g kg − 1 -dose relative to the 0.75 µ g kg − 1 -dose may reflect changing relative bioavailability, which increased from ∼ 48% at 0.75 µ g kg − 1 to 78% at 8.0 µ g kg − 1 . The covariate analysis showed that increasing body weight may be related to increasing clearance and central compar tment 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. ConclusionThe 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.

Time‐dependent clearance and hematological pharmacodynamics upon erythropoietin multiple dosing in rats

“…We explain our contradictory results by: first the difference in the age of the animals in (A) and (B), and second, the interanimal and/or occasion variabilities. Because the body weight is accounted for in our PK parameters, the correlation between body weight and EPO clearance that was previously established [25,26] may not be considered as an influence factor to explain our observed differences.…”

Population Pharmacokinetics of Darbepoetin Alfa in Conjunction with Hypothermia for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy

“…A majority of the adult pharmacokinetic studies pooled data from patients who received darbepoetin alfa intravenously and via subcutaneous injection [34–36]. These studies used a two-compartment model to describe darbepoetin alfa pharmacokinetics [34–36].…”

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

“…In adults, Darbe demonstrated even slower absorption, reaching its peak at around 54.1 h after s.c. administration 3 . The absorption rate constant of Darbe in infants following s.c. administration estimated using our model was 0.062 L/h, and the absorption half-life was 11.2 h. The absorption rate constant of Darbe (ka) in adults was reported to be 0.0212 L/h, 17 corresponding to an absorption half-life of 32.7 h. The higher ka value and shorter absorption half-life in infants reflect a much faster absorption process than in adults, which is consistent with the observed data. The lymphatic system represents a major route for the absorption of protein drugs, including Epo 18 , 19 .…”

“…Agoram et al 17 performed population pharmacokinetic analysis to characterize Darbe disposition in healthy adults and reported that Darbe pharmacokinetics in adults was well described by a 2-compartment model, with clearance equal to 0.00234 L/h/kg and volume of distribution of central compartment equal to 0.085 L/kg. However, in contrast to the pharmacokinetic parameters in adults, our study revealed a clearance of Darbe in infants that is much more rapid (0.05 L/h/kg, in male infants, and 0.031 L/h/kg in female infants) and that the volume of distribution is much greater (0.84 L/kg).…”