A comparison of nonlinear pharmacokinetics of erythropoietin in sheep and humans

The primary mechanism of erythropoietin's (EPO) in vivo elimination and the tissue, or tissues, responsible are unknown. Previous studies indicating t hat EPO pharmacokinetic (PK) behaviour is nonlinear suggest that EPO elimin ation takes place by a saturable mechanism. A versatile PK system analysis, the Disposition Decomposition Analysis (DDA), capable of quantification of the Michaelis-Menten parameters, V-m and k(m) was used to analyze and comp are EPO's PK behaviour in newborn sheep and preterm infants. Lambs and infa nts both demonstrated nonlinear PK behaviour appropriately analyzed with DD A. Compared to preterm infants, lambs had significantly greater (p < 0.05) elimination capacity as determined by the V-m (2789 +/- 525 versus 1767 +/- 250 mU/mL per h (mean +/- S.E.), respectively), and larger extrapolated li near clearances (116 +/- 19.1 versus 21.3 +/- 1.75 mL/kg per h, respectivel y) (p < 0.01). Lambs also demonstrated significantly larger (p < 0.01) degr ees of nonlinearity as judged by smaller mean k(m) values (2142 +/- 258 ver sus 6796 +/- 1.007 mU/mL, respectively). Of note, although the DDA does not distinguish what the mechanism of EPO elimination is, enzymatic degradatio n and receptor-mediated cellular internalization are two possibilities. The in vivo DDA-derived k(m) values were similar to reported in vitro binding affinity k(d) data for erythroid progenitors and cell Lines having EPO-R's, i.e. 240-2400 mU/mL. The present study's demonstration that EPO's nonlinea r PK behaviour in both sheep and humans can be analyzed by the DDA methodol ogy indicates that the Sheep model may be used in invasive studies needed t o further characterize the mechanism of EPO elimination. (C) 1999 John Wile y & Sons, Ltd.