The antiviral effects of RSV fusion inhibitor, MDT‐637, on clinical isolates, vs its achievable concentrations in the human respiratory tract and comparison to ribavirin

摘要

Abstract BackgroundRespiratory syncytial virus (RSV) viral load and disease severity associate, and the timing of viral load and disease run in parallel. An antiviral must be broadly effective against the natural spectrum of RSV genotypes and must attain concentrations capable of inhibiting viral replication within the human respiratory tract. ObjectivesWe evaluated a novel RSV fusion inhibitor, MDT-637, and compared it with ribavirin for therapeutic effect in vitro to identify relative therapeutic doses achievable in humans. MethodMDT-637 and ribavirin were co-incubated with RSV in HEp-2 cells. Quantitative PCR assessed viral concentrations; 50% inhibitory concentrations (IC₅₀) were compared to achievable human MDT-637 and ribavirin peak and trough concentrations. Results and conclusionsThe IC₅₀ for MDT-637 and ribavirin (against RSV-A Long) was 1.42 and 16?973?ng/mL, respectively. The ratio of achievable peak respiratory secretion concentration to IC₅₀ was 6041-fold for MDT-637 and 25-fold for aerosolized ribavirin. The ratio of trough concentration to IC₅₀ was 1481-fold for MDT-637 and 3.29-fold for aerosolized ribavirin. Maximal peak and trough levels of oral or intravenous ribavirin were significantly lower than their IC₅₀s. We also measured MDT-637 IC₅₀s in 3 lab strains and 4 clinical strains. The IC₅₀s ranged from 0.36 to 3.4?ng/mL. Achievable human MDT-637 concentrations in respiratory secretions exceed the IC₅₀s by factors from hundreds to thousands of times greater than does ribavirin. Furthermore, MDT-637 has broad in vitro antiviral activity on clinical strains of different RSV genotypes and clades. Together, these data imply that MDT-637 may produce a superior clinical effect compared to ribavirin on natural RSV infections.