Open AccessThe antiviral effects of RSV fusion inhibitor, MDT ‐637, on clinical isolates, vs its achievable concentrations in the human respiratory tract and comparison to ribavirin
Author(s) -
Kim YoungIn,
Pareek Rajat,
Murphy Ryan,
Harrison Lisa,
Farrell Eric,
Cook Robert,
DeVincenzo John
Publication year - 2017
Publication title -
influenza and other respiratory viruses
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.743
H-Index - 57
eISSN - 1750-2659
pISSN - 1750-2640
DOI - 10.1111/irv.12503
Subject(s) - ribavirin , viral load , respiratory system , virology , respiratory tract infections , respiratory tract , paramyxoviridae , mononegavirales , medicine , aerosolization , virus , viral disease , hepatitis c virus , inhalation , anatomy
Background Respiratory 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. Objectives We 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. Method MDT ‐637 and ribavirin were co‐incubated with RSV in HE p‐2 cells. Quantitative PCR assessed viral concentrations; 50% inhibitory concentrations ( IC 50 ) were compared to achievable human MDT ‐637 and ribavirin peak and trough concentrations. Results and conclusions The IC 50 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 IC 50 was 6041‐fold for MDT ‐637 and 25‐fold for aerosolized ribavirin. The ratio of trough concentration to IC 50 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 IC 50 s. We also measured MDT ‐637 IC 50 s in 3 lab strains and 4 clinical strains. The IC 50 s ranged from 0.36 to 3.4 ng/mL. Achievable human MDT ‐637 concentrations in respiratory secretions exceed the IC 50 s 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.