Population pharmacokinetics of darbepoetin alfa in healthy subjects

Abstract

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 microg kg(-1), or either 80 or 500 microg). 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 microg kg(-1)-dose relative to the 0.75 microg kg(-1)-dose may reflect changing relative bioavailability, which increased from approximately 48% at 0.75 microg kg(-1) to 78% at 8.0 microg 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.

Figure 1

Exploratory graphics analysis of data. (a) Mean of model development dataset serum darbepoetin alfa concentration profiles, 0.75 µg/kg SC, IV (n = 4) (), 8 µg/kg (n = 10) (), 6.5 µg/kg (n = 10) (), 5 µg/kg (n = 6) (), 3 µg/kg (n = 6) (), 2 µg/kg (n = 6) (), 1 µg/kg (n = 28) (), (b) change in exposure measured by dose-normalized AUC_0–∞ (□) and C_max (✦), along with the standard deviations and number of subjects are plotted against administered darbepoetin alfa s.c. dose; (c) mean (+ SD) of model evaluation dataset serum concentration–time profiles after first and second doses for selected dose groups. 500 µg (n = 4–10) (•), 6.5 µg/kg (n = 5–10) (), 3 µg/kg (n = 5–10) (▾). n, Number of individual observations at each time point

Figure 2

Pharmacokinetic (PK) parameter–covariate relationships in the base PK model. ETA (η) is the interindividual variance parameter (see equation 1)

Figure 3

Plot of estimated bioavailability vs. dose from the full covariate pharmacokinetic model. Bioavailability was estimated at 0.75, 1.0, 2.0, 3.0, 5.0, 6.5 and 8.0 µg kg⁻¹ doses using the linear equation fit to the data

Figure 4

Diagnostic plots of the full pharmacokinetic model. (a) Mean predicted (PRED) and individual predicted (IPRED) vs. observed (OBS) serum darbepoetin alfa concentrations are plotted on a log scale. The data points represent individual observations. (b) Plot of the weighted residuals (WRES) vs. PRED

Figure 5

Pharmacokinetic (PK) parameter–covariate relationships in the full covariate PK model. ETA (η) is the interindividual variance parameter (see equation 1)

Figure 6

Summary of the fixed-effects prediction. Mean predicted (dotted line) and mean (±SD) observed (solid line) serum darbepoetin alfa concentration–time profiles at the dose levels in the test dataset are shown. 500 µg (•), 6.5 µg/kg (▿), 3 µg/kg (▪), 2 µg/kg (◊), 80 µg (▴), Mean predicted (), Mean (SD) observed (——)

Figure 7

Evaluation of effect size of influential covariates. Darbepoetin alfa serum concentration profiles after a 100-µg fixed dose, simulated using the full covariate model fixed-effect parameters at the extremes of the ranges of the covariates body weight (solid line) and age (hashed line). 50 kg (), 90 kg (), 30 yr (), 80 yr ()