Evaluation of Antiviral Efficacy of Ribavirin, Arbidol, and T-705 (Favipiravir) in a Mouse Model for Crimean-Congo Hemorrhagic Fever

Oestereich, Lisa; Rieger, Toni; Neumann, Melanie; Bernreuther, Christian; Lehmann, Maria; Krasemann, Susanne; Wurr, Stephanie; Emmerich, Petra; Lamballerie, Xavier de; Ölschläger, Stephan; Günther, Stephan

doi:10.1371/journal.pntd.0002804

Cited by 143 publications

(119 citation statements)

References 56 publications

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“…Favipiravir, a pyrazine carboxamide derivative initially developed and approved for treatment against resistant influenza in Japan (10), is a relevant candidate, with several studies demonstrating its effectiveness against different HF viruses in vitro and in rodent models (10)(11)(12)(13)(14)(15)(16)(17)(18). This molecule is an RNA polymerase inhibitor, metabolized intracellularly into the active form favipiravir ribosyl triphosphate, which is thought to prevent viral RNA strand extension and induce lethal mutagenesis (10).…”

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confidence: 99%

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses

Madelain

Guedj

Nguyen

et al. 2017

Antimicrob Agents Chemother

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Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n ϭ 17) or Mauritian (n ϭ 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC 50 ) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentrationdependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC 50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.

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Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses

Madelain

Guedj

Nguyen

et al. 2017

Antimicrob Agents Chemother

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“…T-705 is presently in clinical development as an influenza virus inhibitor in Japan (new drug application filed) and the United States (phase 3 clinical trial) (18). Antiviral activity has been demonstrated against a broad range of negative-strand RNA viruses, such as members of the Picorna-, Arena-, Bunya-, and Filoviridae (25)(26)(27)(28)(29)(30), and positive-strand RNA viruses, such as the Noro-and Flavivirus genera (31,32). Here we evaluated the activity of T-705 against a broad range of paramyxoviruses in vitro and against HMPV in hamsters.…”

mentioning

confidence: 99%

Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses In Vitro and against Human Metapneumovirus in Hamsters

Jochmans

Nieuwkoop

Smits

et al. 2016

Antimicrob Agents Chemother

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T he family Paramyxoviridae contains a number of viruses causing respiratory tract illnesses in humans, which together have a large clinical impact (1). Human metapneumovirus (HMPV), respiratory syncytial virus (RSV), and parainfluenza virus (PIV) infections are responsible for severe acute respiratory illnesses mainly in young children, but also in immunocompromised and elderly individuals, and are-together with the influenza viruses (family Orthomyxoviridae)-the primary viral causes of hospitalizations for severe respiratory tract disease (2-5). No licensed vaccines or effective antiviral treatments are available for these viruses. Measles virus, yet another paramyxovirus, is responsible for a devastating disease which the WHO committed to eradicate with the aid of effective vaccines. However, due to suboptimal immunization levels, resurgences in infections have been detected, and there is no effective antiviral treatment available for measles virusinfected patients (6-8). Paramyxoviruses are well known for their zoonotic potential: avian pneumovirus (AMPV) is the proposed avian ancestor of HMPV, and the avian Newcastle disease virus (NDV) can cause disease-primarily conjunctivitis-in humans (9-11). Multiple novel paramyxoviruses have been detected in bats, including close relatives of human viruses (12, 13), and henipaviruses continue to cause infections in humans in . No licensed vaccines or effective antiviral treatments are available for any of these viruses. The continuous burden of disease associated with human and zoonotic paramyxoviruses argues for the development of antiviral therapies with broad-spectrum activity against all paramyxoviruses.Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamine) is a pyrazine derivative that has demonstrated potent antiviral activity against multiple RNA viruses (18,19). Intracellular host enzymes act upon T-705, converting it to its active form, T-705-4-ribofuranosyl-5-triphosphate (T-705RTP) (20). T-705RTP functions as a purine nucleotide analog that selectively inhibits the RNA-dependent RNA polymerase (RdRp) or causes lethal mutagenesis upon incorporation into the viral RNA (21-24). T-705 is presently in clinical development as an influenza virus inhibitor in Japan (new drug application filed) and the United States (phase 3 clinical trial) (18). Antiviral activity has been demonstrated against a broad range of negative-strand RNA viruses, such as members of the Picorna-, , and positive-strand RNA viruses, such as the Noro-and Flavivirus genera (31, 32). Here we evaluated the activity of T-705 against a broad range of paramyxoviruses in vitro and against HMPV in hamsters. MATERIALS AND METHODS Cells

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“…A study using a mouse model showed that ribavirin and arbidolon did not affect survival, while favipiravir was effective [93] .…”

Section: Treatmentmentioning

confidence: 99%

Crimean-Congo Hemorrhagic Fever

Kazancıoğlu¹,

Akıncı²,

Bodur³

2018

mjima

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Evaluation of Antiviral Efficacy of Ribavirin, Arbidol, and T-705 (Favipiravir) in a Mouse Model for Crimean-Congo Hemorrhagic Fever

Cited by 143 publications

References 56 publications

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses

Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses In Vitro and against Human Metapneumovirus in Hamsters

Crimean-Congo Hemorrhagic Fever

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