PT  - JOURNAL ARTICLE
AU  - Sukyung Woo
AU  - William J. Jusko
TI  - Interspecies Comparisons of Pharmacokinetics and Pharmacodynamics of Recombinant Human Erythropoietin
AID  - 10.1124/dmd.107.015248
DP  - 2007 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1672--1678
VI  - 35
IP  - 9
4099  - http://dmd.aspetjournals.org/content/35/9/1672.short
4100  - http://dmd.aspetjournals.org/content/35/9/1672.full
SO  - Drug Metab Dispos2007 Sep 01; 35
AB  - 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