Population Pharmacokinetics of rHuEpo in Healthy volunteers.

Objectives. rHuEpo (Recombinant Human Erythopoientin-alpha) is approved in the US and EU for treatment of anemia in several indications, including anemia in patients receiving chemotherapy for cancer. The objectives of this analysis were to model rHuEpo pharmacokinetics after intravenous and subcutaneous administration, to quantify the associated variability and to examine the influence of demographic characteristics and other covariates on the pharmacokinetics.

Methods. A population pharmacokinetic analysis was performed using data from sixteen studies where healthy volunteers received doses of rHuEpo, ranging from 1 IU/kg to 160,000IU, as single or repeated administration. Data was available for 49 subjects who received intravenous administration, for 427 subjects who received subcutaneous administration, and for 57 subjects who received placebo. The pharmacokinetic data was rich, with an average of 27 samples per subject. Data was analysed using NONMEM with the first order method.

Results. Endogenous Epo concentrations displayed a diurnal variation, described by the sum of two cosine functions with periods of 24h and 12h. The disposition of rHuEpo was modelled using a two-compartment model with parallel linear and nonlinear clearance. The absorption after subcutaneous administration was described by a complex model, where the main fraction of the dose was absorbed via a short sequential zero-first order process and the remainder was absorbed via a long-lasting zero-order process. The bioavailability increased with increasing dose. Interindividual and interoccasion variability were characterized. The influence of several covariates on rHuEpo pharmacokinetics could be identified, the most important being the influence of age on the first order absorption rate.

Conclusions. This model establishes a model describing rHuEpo pharmacokinetics in healthy volunteers after both intravenous and subcutaneous administration, covering a very wide dose-range and a number of different treatment regimens. The model will serve as a basis for PK/PD modelling of rHuEpo, and for further establishing its pharmacokinetics in cancer patients.