Received for publication February 20, 2007.
Revised June 12, 2007.
Accepted for publication June 13, 2007.

Interspecies comparisons of pharmacokinetics and pharmacodynamics of recombinant human erythropoietin (rHuEPO)

Abstract

Erythropoietin (EPO) has a highly conserved structure among mammals, and thus recombinant human erythropoietin (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 (V_ss) after intravenous (i.v.) doses of rHuEPO were obtained in several species via non-compartmental analysis and were assessed using the traditional allometric approach. Also, PK/PD modeling of rHuEPO concentrations and responses (reticulocytes, RBC, and hemoglobin) was performed following a range of i.v. and s.c. doses in rats, monkeys, and humans. Nonlinear disposition (V_max, K_m), and s.c. absorption rate and bioavailability parameters of rHuEPO were examined. A cascade, indirect, lifespan PD model was applied to recover efficacy (S_max) and potency (SC₅₀) of rHuEPO on erythropoiesis, and erythroid cell lifespan parameters. Despite nonlinear rHuEPO disposition, CL and V_ss were highly correlated with body weight (R² >0.92) with allometric scaling exponents of 0.708 for CL and 0.853 for V_ss. The s.c. bioavailability increased with dose in monkey and human but appeared to be dose-independent in rats. A correlation between S_max 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.

Key words: absorption, bioavailability, pharmacokinetic/pharmacodynamic modeling, recombinant proteins