Development of a pharmacokinetic pharmacodynamic (PKPD) model to predict onset of hemolytic anemia in (PEG)interferon/ribavirin treated hepatitis–C virus (HCV)-infected patients

Abstract

Purpose A significant side-effect of HCV treatment with interferon (IFN)/ribavirin (RBV) therapy is hemolytic anemia, which can result in RBV dose reduction and may compromise efficacy. Darbepoetin alfa (DA) is an erythropoiesis stimulating protein approved for the treatment of anemia associated with renal insufficiency and cancer. The goal of the current work was to use PKPD modeling to predict onset of anemia in HCV patients on antiviral treatment. Methods The PKPD model used was a physiologically based indirect response model wherein the erythropoietic agent's concentration stimulates production of erythrocyte progenitors. The model structure was modified to account for hemolytic anemia using a first-order rate equation, and subsequent up-regulation of endogenous erythropoietin using a Michaelis-Menten type equation. PD model parameters were obtained using hemoglobin (Hb) data from patients on antiviral therapy treated with rHuEPO, and then modified to allow predictions for DA. Results PKPD model simulations predicted that about 60% of patients on antiviral therapy were likely to become anemic (Hb< 12 g/dL) median time to onset of anemia was 4 weeks 25% were likely to require RBV dose reduction (Hb<10 g/dL) if anemia was untreated. Conclusions PKPD modeling was useful in predicting onset of anemia in HCV patients undergoing antiviral treatment. The model aided in the design of a clinical trial to explore the use of DA to treat anemia due to antiviral therapy. Clinical Pharmacology & Therapeutics (2004) 75, P78–P78; doi: 10.1016/j.clpt.2003.11.296