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Influenza Other Respir Viruses. 2017 Nov;11(6):525-530. doi: 10.1111/irv.12503. Epub 2017 Oct 30.

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.

Author information

1
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.
2
Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, TN, USA.
3
College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
4
Teva Global Respiratory R&D, Teva Pharmaceuticals, Monmouth Junction, NJ, USA.
5
Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.

Abstract

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 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 CONCLUSIONS:

The 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 IC50 s. We also measured MDT-637 IC50 s in 3 lab strains and 4 clinical strains. The IC50 s ranged from 0.36 to 3.4 ng/mL. Achievable human MDT-637 concentrations in respiratory secretions exceed the IC50 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.

KEYWORDS:

antiviral; bronchiolitis; fusion inhibitor; pharmacokinetics; respiratory syncytial virus; ribavirin

PMID:
28990339
PMCID:
PMC5705693
DOI:
10.1111/irv.12503
[Indexed for MEDLINE]
Free PMC Article

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