Abstract
The primary objective of this work was to determine the optimal time for administration of an erythropoietin (Epo) dose to maximize the erythropoietic effect using a simulation study based on a young sheep pharmacodynamic model. The dosing optimization was accomplished by extending a Hb production pharmacodynamic model, which evaluates the complex dynamic changes in the Epo receptor (EpoR) pool from the changes in Epo clearance. Fourteen healthy 2-month-old sheep were phlebotomized to Hb levels of 3 to 4 g/dl. Epo clearance was evaluated longitudinally in each animal by administering tracer doses of 125I-recombinant human Epo multiple times during the experiment. Kinetic parameters were estimated by simultaneously fitting to Hb data and Epo clearance data. The phlebotomy caused a rapid temporary increase in the endogenous Epo plasma level. The Hb began to increase after the increased in the Epo level with a lag time of 1.13 ± 0.79 days. The average correlation coefficients for the fit of the model to the Hb and clearance data were 0.953 ± 0.018 and 0.876 ± 0.077, respectively. A simulation study was done in each sheep with fixed individual estimated model parameters to determine the optimal time to administer a 100 U/kg intravenous bolus Epo dose. The optimal dose administration time was 11.4 ± 6.2 days after phlebotomy. This study suggests that the Hb produced from Epo administration can be optimized by considering the dynamic changes in the EpoR pool.
Footnotes
This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Program Project Grant 2 P01-HL046925-11A1]; and the Children's Miracle Network Telethon of Iowa.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.036855.
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ABBREVIATIONS:
- Epo
- erythropoietin
- EpoR
- erythropoietin receptor
- PK/PD
- pharmacokinetic/pharmacodynamic
- rhEpo
- recombinant human erythropoietin
- RBC
- red blood cell.
- Received October 20, 2010.
- Accepted April 1, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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