Pharmacokinetic differentiation of drug candidates using system analysis and physiological-based modelling. Comparison of C.E.R.A. and erythropoietin.

Evaluation of the pharmacokinetics (PKs) in a proper physiological context is paramount to elucidate the factors that may improve a drug's PK properties. Using modern system analysis-based physiological modelling principles, this work applies a novel kinetic analysis framework to a PK comparison of two erythropoietically active drugs, C.E.R.A. (continuous erythropoietin receptor activator) and recombinant human erythropoietin (Epo), aimed at elucidating the main factors responsible for the substantial PK differences seen. The evaluation according to the new model is compared with a compartmental model analysis. Sheep (n = 7 for Epo; n = 8 for C.E.R.A.) received intravenous bolus injections of Epo and C.E.R.A. Baseline and 20-30 blood samples per injection were assayed by radioimmunoassay. Fundamental physiologically based PK building block principles were introduced, proceeding to the construction of a general PK model and several sub-models from which a final PK model was selected based on information theoretical principles. The compartmental comparison analysis use a two-compartment model with central Michaelis-Menten elimination. Several lines of evidence support the hypothesis that the desirable slow elimination of C.E.R.A. relative to Epo is mainly caused by a smaller recirculation extraction fraction, which appears more influential on the elimination kinetics than the mean circulation transit time. The compartmental analysis demonstrates large differences in several PK parameters that contribute to C.E.R.A.'s slower elimination, consistent with the recirculation model analysis. It is hypothesized that C.E.R.A.'s smaller recirculatory extraction fraction is due to a reduced receptor-mediated elimination, consistent with in-vitro measurements where C.E.R.A. shows Epo-receptor binding with a lower association constant and a larger dissociation constant.