Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection

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Abstract

Objectives

Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for the treatment of influenza virus infection. We evaluated the efficacy of delayed oral treatment with baloxavir marboxil in combination with a neuraminidase inhibitor in a mouse model of lethal influenza virus infection.

Methods

The inhibitory potency of baloxavir acid (the active form of baloxavir marboxil) in combination with neuraminidase inhibitors was tested in vitro. The therapeutic effects of baloxavir marboxil and oseltamivir phosphate, or combinations thereof, were evaluated in mice lethally infected with influenza virus A/PR/8/34; treatments started 96 h post-infection.

Results

Combinations of baloxavir acid and neuraminidase inhibitor exhibited synergistic potency against viral replication by means of inhibition of cytopathic effects in vitro. In mice, baloxavir marboxil monotherapy (15 or 50 mg/kg twice daily) significantly and dose-dependently reduced virus titre 24 h after administration and completely prevented mortality, whereas oseltamivir phosphate treatments were not as effective. In this model, a suboptimal dose of baloxavir marboxil (0.5 mg/kg twice daily) in combination with oseltamivir phosphate provided additional efficacy compared with monotherapy in terms of virus-induced mortality, elevation of cytokine/chemokine levels and pathological changes in the lung.

Conclusions

Baloxavir marboxil monotherapy with 96 h-delayed oral dosing achieved drastic reductions in virus titre, inflammatory response and mortality in a mouse model. Combination treatment with baloxavir acid and oseltamivir acid in vitro and baloxavir marboxil and oseltamivir phosphate in mice produced synergistic responses against influenza virus infections, suggesting that treating humans with the combination may be beneficial.

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Most cited references 24

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Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

P Talalay, T C Chou (1984)

A generalized method for analyzing the effects of multiple drugs and for determining summation, synergism and antagonism has been proposed. The derived, generalized equations are based on kinetic principles. The method is relatively simple and is not limited by whether the dose-effect relationships are hyperbolic or sigmoidal, whether the effects of the drugs are mutually exclusive or nonexclusive, whether the ligand interactions are competitive, noncompetitive or uncompetitive, whether the drugs are agonists or antagonists, or the number of drugs involved. The equations for the two most widely used methods for analyzing synergism, antagonism and summation of effects of multiple drugs, the isobologram and fractional product concepts, have been derived and been shown to have limitations in their applications. These two methods cannot be used indiscriminately. The equations underlying these two methods can be derived from a more generalized equation previously developed by us (59). It can be shown that the isobologram is valid only for drugs whose effects are mutually exclusive, whereas the fractional product method is valid only for mutually nonexclusive drugs which have hyperbolic dose-effect curves. Furthermore, in the isobol method, it is laborious to find proper combinations of drugs that would produce an iso-effective curve, and the fractional product method tends to give indication of synergism, since it underestimates the summation of the effect of mutually nonexclusive drugs that have sigmoidal dose-effect curves. The method described herein is devoid of these deficiencies and limitations. The simplified experimental design proposed for multiple drug-effect analysis has the following advantages: It provides a simple diagnostic plot (i.e., the median-effect plot) for evaluating the applicability of the data, and provides parameters that can be directly used to obtain a general equation for the dose-effect relation; the analysis which involves logarithmic conversion and linear regression can be readily carried out with a simple programmable electronic calculator and does not require special graph paper or tables; and the simplicity of the equation allows flexibility of application and the use of a minimum number of data points. This method has been used to analyze experimental data obtained from enzymatic, cellular and animal systems.

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Neuraminidase inhibitors for influenza.

Anne Moscona (2005)

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Estimates of deaths associated with seasonal influenza --- United States, 1976-2007.

David Shay (2010)

Influenza infections are associated with thousands of deaths every year in the United States, with the majority of deaths from seasonal influenza occurring among adults aged >or=65 years. For several decades, CDC has made annual estimates of influenza-associated deaths, which have been used in influenza research and to develop influenza control and prevention policy. To update previously published estimates of the numbers and rates of influenza-associated deaths during 1976-2003 by adding four influenza seasons through 2006-07, CDC used statistical models with data from death certificate reports. National mortality data for two categories of underlying cause of death codes, pneumonia and influenza causes and respiratory and circulatory causes, were used in regression models to estimate lower and upper bounds for the number of influenza-associated deaths. Estimates by seasonal influenza virus type and subtype were examined to determine any association between virus type and subtype and the number of deaths in a season. This report summarizes the results of these analyses, which found that, during 1976-2007, estimates of annual influenza-associated deaths from respiratory and circulatory causes (including pneumonia and influenza causes) ranged from 3,349 in 1986-87 to 48,614 in 2003-04. The annual rate of influenza-associated death in the United States overall during this period ranged from 1.4 to 16.7 deaths per 100,000 persons. The findings also indicated the wide variation in the estimated number of deaths from season to season was closely related to the particular influenza virus types and subtypes in circulation.

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Author and article information

Journal

Journal ID (nlm-ta): J Antimicrob Chemother

Journal ID (iso-abbrev): J. Antimicrob. Chemother

Journal ID (publisher-id): jac

Title: Journal of Antimicrobial Chemotherapy

Publisher: Oxford University Press

ISSN (Print): 0305-7453

ISSN (Electronic): 1460-2091

Publication date (Print): March 2019

Publication date (Electronic): 21 November 2018

Publication date PMC-release: 21 November 2018

Volume: 74

Issue: 3

Pages: 654-662

Affiliations

[1 ]Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan

[2 ]Shionogi TechnoAdvance Research, Co., Ltd., Osaka, Japan

Author notes

Corresponding author. Tel: +81-6-6331-8489; E-mail: keita.fukao@ 123456shionogi.co.jp

Article

Publisher ID: dky462

DOI: 10.1093/jac/dky462

PMC ID: 6376846

PubMed ID: 30476172

SO-VID: f8c07e61-39dd-4bfd-94da-ed690d6435d9

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 29 June 2018

Date revision requested : 24 August 2018

Date revision received : 09 October 2018

Date accepted : 13 October 2018

Page count

Pages: 9

Funding

Funded by: Shionogi and Co., Ltd

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Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection

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Abstract

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Karger: Oncology

Most cited references 24

Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

Neuraminidase inhibitors for influenza.

Estimates of deaths associated with seasonal influenza --- United States, 1976-2007.

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