The co-administration of telaprevir increases ribavirin plasma and intra-erythrocytic concentrations, causing higher onset of anemia

Introduction: The new standard of care (SOC) for treatment of HCV-1 is the association of Telaprevir (TEL) or Boceprevir (BOC) to Ribavirin (RBV) and Peg-Interferon alfa. Despite the improved efficacy, a higher frequency of hemolytic anemia was observed. Anemia is a typical side effect of RBV. Aim: Our aim was to investigate the existence of a concentration-dependent interaction between TEL and RBV. Materials and methods: To evaluate this possible interaction 17 patients treated with SOC were compared to 119 with dual therapy. Moreover, the same comparison was performed in a sub-group of 9 out of 17 patientswhowere treated 1-2 years before with dual therapy, and recently re-treated with SOC. This comparison provided data without interferences due to the inter-patient variability. RBV plasma and intra-erythrocytic levels and TEL (–S and –R isomers) plasma concentrations were determined after 4 weeks of therapy with validated chromatographic methods. Results: No significant differences in weight-based dose of RBV were observed between therapies. In the 9 patients sub-group, both RBV plasma and intra-erythrocytic concentrations were significantly higher during retreatment (p = 0.015 and p = 0.012, respectively). This evidence was confirmed for intra-erythrocytic concentrations in the overall treated patients (p = 0.040). Triple therapy treated patients showed a higher incidence of anemia (88% vs. 37%, p < 0.001). Interestingly, a significant correlation (p = 0.023) emerged between hemoglobin drop andRBVplasma concentration. Moreover, RBV and TEL-S plasma concentrations were significantly (p = 0.008) correlated. Conclusions: The co-administration of TEL increased RBV concentrations in a concentration-dependent manner, leading to a higher incidence of anemia. This unbiased evidence highlights the need of specific cut-off values for RBV and TEL-S concentrations. These evidences justify the use of Therapeutic Drug Monitoring (TDM) to manage toxicity, guiding the “ongoing” dose modification to maintain patients on therapy.