Abstract
A pharmacokinetics (PK)/pharmacodynamics (PD) model was developed to describe the tolerance and rebound for reticulocyte (RET) and red blood cell (RBC) counts and the hemoglobin (Hb) concentrations in blood after repeated intravenous administrations of 1350 IU/kg of recombinant human erythropoietin (rHuEPO) in rats thrice weekly for 6 weeks. Drug concentrations were described by using a quasi-equilibrium model. The PD model consisted of a lifespan-based indirect response model (LIDR) with progenitor cells [burst colony-forming unit erythroblasts and colony-forming unit erythroblasts (CFUs)], normoblasts (NOR), RETs, and RBCs. Drug–receptor complex stimulatory effects on progenitor cells differentiation and RBC lifespan were expressed by using the Emax model (Smax-epo and SC50-epo, Emax and EC50). The Hb profile was indirectly modeled through a LIDR model for mean corpuscular hemoglobin (with a lifespan Tmch) including a linear (Smax-mch) drug stimulatory effect. The negative feedback from RBCs accounted for the time-dependent rHuEPO clearance decline. A simultaneous PK/PD fitting was performed by using MATLAB-based software. PK parameters such as equilibrium dissociation, erythropoietin receptor degradation, production, and internalization rate constants were 0.18 nM (fixed), 0.08 h−1, 0.03 nM/h, and 2.51 h−1, respectively. The elimination rate constant and central volume of distribution were 0.57 h−1 and 40.63 ml/kg, respectively. CFU and NOR, RET, and RBC lifespans were 37.26 h, 17.25 h, and 30.15 days, respectively. Smax-epo and SC50-epo were 7.3 and 0.47 10−2 nM, respectively. Emax was fixed to 1. EC50 and SC50-epo were equal. Smax-mch and Tmch were 168.1 nM−1 and 35.15 days, respectively. The proposed PK/PD model effectively described rHuEPO nonstationary PK and allowed physiological estimates of cell lifespans.
Footnotes
This work was supported by a Fellowship in Pharmacokinetics and Pharmacodynamics from Amgen Inc.; and the National Institutes of Health National Institutes of General Medical Sciences [Grant GM57980].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.167304.
-
ABBREVIATIONS:
- PK
- pharmacokinetics
- PD
- pharmacodynamics
- BFU
- burst colony-forming unit erythroblast
- CFU
- colony-forming unit erythroblast
- NOR
- normoblast
- CLlin
- linear clearance
- CLrec
- receptor-mediated clearance
- CLTotal
- total body clearance
- MCH
- mean corpuscular hemoglobin
- RBC
- red blood cell
- MLRBC
- mean lifespan of RBCs
- RET
- reticulocyte
- EPO
- erythropoietin
- rHuEPO
- recombinant human EPO
- EPOR
- EPO receptor
- ELISA
- enzyme-linked immunosorbent assay
- TMDD
- target-mediated drug disposition
- QE
- quasi-equilibrium
- CV
- coefficient of variation
- AUC
- area under rHuEPO concentrations curve
- AUMC
- area under moment curve.
- Received February 18, 2010.
- Accepted May 24, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|