Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Dose Administration in Cynomolgus Monkeys
Rohini Ramakrishnan, Wing K. Cheung, Francis Farrell, Linda Joffee and William J. Jusko
Journal of Pharmacology and Experimental Therapeutics July 2003, 306 (1) 324-331; DOI: https://doi.org/10.1124/jpet.102.047191
Rohini Ramakrishnan
Wing K. Cheung
Francis Farrell
Linda Joffee
William J. Jusko
The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEpo) were investigated in monkeys. A two-compartment model with dual input and nonlinear disposition could adequately characterize the PK of rHuEpo upon three intravenous and six s.c. administrations. The kinetic model suggests rapid zero-order absorption of part of the s.c. dose (35%) followed by a slow first-order entry through the lymphatics. The s.c. treatments caused a delayed dose-dependent rise in reticulocyte numbers peaking between 100 and 200 h and returning to baseline by 300 to 400 h. This was followed by steady rises in red blood cell (RBC) and hemoglobin counts. A physiological catenary model based on a life span concept with rHuEpo stimulating the production of two cell populations (progenitor cells and erythroblasts) was applied. The model could adequately describe the reticulocyte responses upon the various s.c. treatments, giving estimates of maturation times for cells in the various stages of differentiation including the early progenitor cells (70.4 h), erythroblasts (15.0 h), and reticulocytes (141.6 h) that are close to the literature reported values. An Smax of 3.13 was estimated indicating a moderate maximum stimulation of erythropoiesis, whereas the SC50 was 842 IU/l. The model was used to effectively predict the increases in RBC and hemoglobin counts as well. In conclusion, the physiological PK/PD model developed could adequately describe the time course of rHuEpo effects, yielding realistic estimates of cell life span parameters.
This study was supported by R. W. Johnson Pharmaceutical Research Institute (Raritan, NJ) and by Grant GM-57980 from the National Institute of General Medical Sciences, National Institutes of Health.
DOI: 10.1124/jpet.102.047191.
ABBREVIATIONS: Epo, erythropoietin; rHuEpo, recombinant human erythropoietin; PK/PD, pharmacokinetic/pharmacodynamic; RBC, red blood cell.
Received November 21, 2002.
Accepted March 28, 2003.
You are going to email the following Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Dose Administration in Cynomolgus Monkeys
Journal of Pharmacology and Experimental Therapeutics July 1, 2003, 306 (1) 324-331; DOI: https://doi.org/10.1124/jpet.102.047191
Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation
Enhanced Hepatic Uptake and Bioactivity of Type α1(I) Collagen Gene Promoter-Specific Triplex-Forming Oligonucleotides after Conjugation with Cholesterol
Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana
Show more ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION