TY - JOUR T1 - A pharmacodynamic analysis of receptor-based dosing optimization of erythropoietin efficacy JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.110.036855 SP - dmd.110.036855 AU - Matthew Rosebraugh AU - John Widness AU - Peter Veng-Pedersen Y1 - 2011/01/01 UR - http://dmd.aspetjournals.org/content/early/2011/04/01/dmd.110.036855.abstract N2 - The primary objective of this work is 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 hemoglobin (Hb) production pharmacodynamic model, which evaluates the complex dynamic changes in the EpoR pool from the changes in Epo clearance. Fourteen healthy two month old sheep were phlebotomized to Hb levels of 3-4 g/dL. Epo clearance was evaluated longitudinally in each animal by administering tracer doses of 125I-rhEpo 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 following the increased in the Epo level with a lag time of 1.13±0.79 days. The average correlation coefficient for the fit of the model to the Hb and clearance data was 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 100U/Kg IV bolus Epo dose. The optimal dose administration time was 11.4±6.2 days post phlebotomy. This study suggests that the Hb produced from Epo administration can be optimized by considering the dynamic changes in the EpoR pool. ER -