835 Exposure-Response Relationships in Telaprevir Combination Therapy in Treatment-NaïVE Genotype 1 Chronic HCV Patients

Abstract

Introduction: Telaprevir (TVR) in combination with peginterferon alfa-2a (Peg-IFN) and ribavirin (RBV) was recently approved in the United States, Canada, Europe, and Japan for the treatment of genotype 1 chronic HCV infection. The relationship between drug exposure and safety and efficacy parameters is unclear. We evaluated relationships between efficacy and safety and concentrations of TVR, RBV, and Peg-IFN. Methods: Treatment-naive patients (N=472, ADVANCE/ILLUMINATE) who were assigned 12-weeks TVR combination therapy with 24or 48-weeks total PR and had PK data available were included. Using generalized linear modeling (logistic regression) and receiver operating characteristic (ROC) analyses, we investigated associations between drug exposures, eRVR, SVR, anorectal symptoms, and certain subsets of anemia (defined by DAIDS toxicity grading) and rash. Population PK model-predicted average steady-state TVR concentrations, the observed Week-4 RBV (plasma) concentrations, and observed Week-4 Peg-IFN (serum) concentrations were representative exposure measures. Results: eRVR and SVR weakly correlated with TVR, RBV, and Peg-IFN exposure. With increasing exposure, each drug exhibited a shallow, non-significant increase in eRVR and SVR probability. Anemia incidence during the TVR-phase correlated with TVR, RBV and Peg-IFN exposure, and correlated most strongly with RBV exposure. No drug exposures strongly correlated with rash or anorectal symptoms during the TVR-phase.