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Drug Metabolism and Disposition Fast Forward
First published on June 18, 2007; DOI: 10.1124/dmd.107.015248

0090-9556/07/3509-1672-1678$20.00
DMD 35:1672-1678, 2007

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Interspecies Comparisons of Pharmacokinetics and Pharmacodynamics of Recombinant Human Erythropoietin

Sukyung Woo, and William J. Jusko

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York

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.

Address correspondence to: William J. Jusko, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 565 Hochstetter Hall, State University of New York at Buffalo, Buffalo, NY 14260. E-mail: wjjusko{at}buffalo.edu






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