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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.
J Antimicrob Chemother. 2019 03 01; 74(3):654-662.JA

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.

Authors+Show Affiliations

Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.Shionogi TechnoAdvance Research, Co., Ltd., Osaka, Japan.Shionogi TechnoAdvance Research, Co., Ltd., Osaka, Japan.Shionogi TechnoAdvance Research, Co., Ltd., Osaka, Japan.Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30476172

Citation

Fukao, Keita, et al. "Combination Treatment With the Cap-dependent Endonuclease Inhibitor Baloxavir Marboxil and a Neuraminidase Inhibitor in a Mouse Model of Influenza a Virus Infection." The Journal of Antimicrobial Chemotherapy, vol. 74, no. 3, 2019, pp. 654-662.
Fukao K, Noshi T, Yamamoto A, et al. Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection. J Antimicrob Chemother. 2019;74(3):654-662.
Fukao, K., Noshi, T., Yamamoto, A., Kitano, M., Ando, Y., Noda, T., Baba, K., Matsumoto, K., Higuchi, N., Ikeda, M., Shishido, T., & Naito, A. (2019). Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection. The Journal of Antimicrobial Chemotherapy, 74(3), 654-662. https://doi.org/10.1093/jac/dky462
Fukao K, et al. Combination Treatment With the Cap-dependent Endonuclease Inhibitor Baloxavir Marboxil and a Neuraminidase Inhibitor in a Mouse Model of Influenza a Virus Infection. J Antimicrob Chemother. 2019 03 1;74(3):654-662. PubMed PMID: 30476172.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection. AU - Fukao,Keita, AU - Noshi,Takeshi, AU - Yamamoto,Atsuko, AU - Kitano,Mitsutaka, AU - Ando,Yoshinori, AU - Noda,Takahiro, AU - Baba,Kaoru, AU - Matsumoto,Kazumi, AU - Higuchi,Naoko, AU - Ikeda,Minoru, AU - Shishido,Takao, AU - Naito,Akira, PY - 2018/06/29/received PY - 2018/10/09/revised PY - 2018/10/13/accepted PY - 2018/11/27/pubmed PY - 2020/5/27/medline PY - 2018/11/27/entrez SP - 654 EP - 662 JF - The Journal of antimicrobial chemotherapy JO - J Antimicrob Chemother VL - 74 IS - 3 N2 - 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. SN - 1460-2091 UR - https://www.unboundmedicine.com/medline/citation/30476172/Combination_treatment_with_the_cap_dependent_endonuclease_inhibitor_baloxavir_marboxil_and_a_neuraminidase_inhibitor_in_a_mouse_model_of_influenza_A_virus_infection_ DB - PRIME DP - Unbound Medicine ER -