2003
Verona, Italy
A Mechanism-Based PK/PD Model Predicts the Time-Course of Hematological responses for Epoetin beta
N. Hayashi(1), K. P. Zuideveld(1), P. Jordan(2), R. Gieschke(1)
(1) Modeling & Simulation Group; (2) Biometrics, F. Hoffmann-La Roche AG, Basel, Switzerland
Objectives: The objective was to develop a Mechanism-Based PK/PD model that predicts the time courses of hematological responses after administration of Epoetin beta using data from a study in healthy volunteers. Furthermore, simulations were used to assess whether the model is able to predict published efficacy data in renal anemia patients.
Methods: The population PK/PD analysis was performed using NONMEM based on serum concentrations of Epoetin beta, reticulocyte, Red Blood Cell (RBC), Hemoglobin (Hb), and Hematocrit (Ht).
The mechanism-based model was developed on the basis of data from a clinical pharmacology study in 43 healthy volunteers. The time profiles of hematological variables in patients were simulated and compared with the published study's results in renal anemia patients.
Results: The model includes the concepts of "an Emax model for the effect of the drug on RBC production rate", "a homeostatic negative feed back by Hb on the RBC production rate", "an identical life span for all RBC", and "the amplified changes in reticulocyte count caused by the immature reticulocyte increase". Population mean values for Emax and EC50 were 4.74 x104/mL/day and 25.2 mIU/mL, respectively. For the simulations of hematological responses in patients, the baseline values of RBC observed in patients were used. As a result, satisfactory predictions for patients were obtained for not only the mean values but also the inter-individual variability in all hematopoietic responses. The observed hematological responses for the patients with renal anemia were within the 80% confidence interval predicted by the model.
Conclusion: A mechanism-based PK/PD model was developed and is able to describe the time courses of hematological responses for Epoetin beta in healthy volunteers and in patients.