title: Receptor-based dosing optimization of erythropoietin in juvenile sheep after phlebotomy.
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 (125)I-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.
authors: Department of Pediatrics, University of Iowa, College of Pharmacy, 115 S. Grand Ave., Iowa City, IA 52242, USA.
authors: Matthew
authors: M
authors: Rosebraugh
authors: John A
authors: JA
authors: Widness
authors: Peter
authors: P
authors: Veng-Pedersen
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018962:Phlebotomy; D012756:Sheep
chemical_list: D004921:Erythropoietin