Telaprevir-S isomer enhances ribavirin exposure and the ribavirin-related haemolytic anaemia in a concentration-dependent manner

• Published in: Antiviral research 2014-09, Vol.109, p.7-14
• Main Authors: De Nicolò, Amedeo, Boglione, Lucio, Ciancio, Alessia, Cusato, Jessica, Strona, Silvia, Cardellino, Chiara Simona, Mohamed Abdi, Adnan, Cariti, Giuseppe, Troshina, Giulia, Caviglia, Gian Paolo, Smedile, Antonina, Rizzetto, Mario, Di Perri, Giovanni, D’Avolio, Antonio
• Format: Article
• Language: English
• Subjects: Adult; Anaemia; Anemia, Hemolytic - chemically induced; Anemias. Hemoglobinopathies; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - adverse effects; Antiviral Agents - therapeutic use; Biological and medical sciences; Diseases of red blood cells; Dose-Response Relationship, Drug; Drug Therapy, Combination - adverse effects; Female; HCV-1; Hematologic and hematopoietic diseases; Hepacivirus - drug effects; Hepacivirus - physiology; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - virology; Human viral diseases; Humans; Infectious diseases; Interaction; Interferon-alpha - adverse effects; Interferon-alpha - therapeutic use; Isomerism; Male; Medical sciences; Middle Aged; Oligopeptides - adverse effects; Oligopeptides - chemistry; Oligopeptides - therapeutic use; Pharmacology. Drug treatments; Ribavirin; Ribavirin - adverse effects; Ribavirin - therapeutic use; Telaprevir; Viral diseases; Viral hepatitis
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2014.06.005

•Confirmation of the telaprevir–ribavirin kinetic interaction.•First genetically unbiased data on the increased ribavirin concentrations.•First identification of the responsible telaprevir isomer for the interaction.•High rate of anaemia onset identified as a strong limit to therapy success.•Indication of TDM as a tool to improve tolerability of triple therapy with telaprevir. The standard-of-care for the treatment of genotype-1 chronic hepatitis C is based on the combination of direct acting antivirals, such as boceprevir and telaprevir, with ribavirin and pegylated-interferon alfa. These triple regimens give a higher response rate than dual therapy, but on the other hand show a more than 10% higher rate of anaemia. Not enough focus has been given to the interaction between telaprevir and RBV. In this work, we aimed to study and deepen this relationship by comparing ribavirin plasma and intra-erythrocytic concentrations at one month of triple and dual therapy (17 vs. 119 patients). Moreover, we determined telaprevir isomers concentrations and tested them for correlation with ribavirin concentrations and haemoglobin loss at one month of treatment. Finally, all drugs concentration data were tested for their correlation with the renal function during treatment. The comparisons of ribavirin concentration and toxicity data were repeated on a sub-group of 9 patients who had been treated 1year before with dual therapy and then re-treated with triple therapy. The observed ribavirin plasma and intra-erythrocytic concentrations in triple therapy were significantly higher compared to dual therapy, both in whole group and sub-group comparison. Ribavirin concentrations were significantly correlated to the haemoglobin loss and telaprevir-S isomer concentrations (r2=0.317 Pvalue=0.023 and r2=0.388 Pvalue=0.008, respectively). Renal function had a significant decrease from the baseline value, but was not significantly correlated with drugs concentrations. These results highlight for the first time that, in the context of triple therapy with telaprevir, ribavirin exposure is related to the telaprevir-S isomer plasma concentration. We conclude that the addition of telaprevir to the dual therapy increases ribavirin exposure and haemoglobin loss: this effect could probably be managed through the therapeutic drug monitoring of ribavirin and telaprevir-S concentrations.