TY - JOUR T1 - Interspecies Comparisons of Pharmacokinetics and Pharmacodynamics of Recombinant Human Erythropoietin JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1672 LP - 1678 DO - 10.1124/dmd.107.015248 VL - 35 IS - 9 AU - Sukyung Woo AU - William J. Jusko Y1 - 2007/09/01 UR - http://dmd.aspetjournals.org/content/35/9/1672.abstract N2 - Erythropoietin (EPO) has a highly conserved structure among mammals, and thus recombinant human EPO (rHuEPO) has biological activity in various species. This study explores the interspecies relationships of the pharmacokinetics (PK) and pharmacodynamics (PD) of rHuEPO. The PK parameters such as clearance (CL) and volume of distribution (Vss) after i.v. doses of rHuEPO were obtained in several species via noncompartmental analysis and were assessed using the traditional allometric approach. Also, PK/PD modeling of rHuEPO concentrations and responses [reticulocytes, red blood cells (RBCs), and hemoglobin] was performed following a range of i.v. and s.c. doses in rats, monkeys, and humans. Nonlinear disposition (Vmax, Km) and s.c. absorption rate and bioavailability parameters of rHuEPO were examined. A cascade, indirect, lifespan PD model was applied to recover efficacy (Smax) and potency (SC50) of rHuEPO on erythropoiesis and erythroid cell lifespan parameters. Despite nonlinear rHuEPO disposition, CL and Vss were highly correlated with body weight (R2 > 0.92) with allometric scaling exponents of 0.708 for CL and 0.853 for Vss. The s.c. bioavailability increased with dose in monkeys and humans but appeared to be dose-independent in rats. A correlation between Smax or SC50 and body weight was not obvious. However, RBC lifespans obeyed allometric principles. Size dependence was found for PK and lifespan parameters, whereas pharmacologic parameters were independent of body weight. The American Society for Pharmacology and Experimental Therapeutics ER -