Ebola virus dynamics in mice treated with favipiravir

Madelain, Vincent; Oestereich, Lisa; Graw, Frederik; Nguyen, Thi Huyen Tram; Lamballerie, Xavier de; Günther, Stephan; Guedj, Jérémie

doi:10.1016/j.antiviral.2015.08.015

Cited by 60 publications

(62 citation statements)

References 23 publications

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“…More generally, the exposure-response relationship cannot be anticipated, and a PK-virus dynamic analysis, as proposed, for instance, for mice infected with EBOV (35), will be needed to fully characterize the antiviral activity of favipiravir. In this respect, viral dynamic modeling teaches that the time of treatment initiation is critical to reduce virus levels and that a drug affecting viral replication, such as favipiravir, will have only a very limited impact on viremia if it is administered after peak viremia (35). Furthermore, the duration of treatment may also be critical, as previous studies showed that EBOV-infected macaques treated with BCX4430 or ZMapp may still have detectable viremia at 14 days postchallenge (36,37).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…However, only a few of these compounds have shown protection in animal models of EBOV, which is a critical step for screening potential drug candidates for future human clinical trials (3,5,6). One class of compounds that has emerged with many promising antiviral candidates is the group of flavonoid molecules.…”

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confidence: 99%

Prophylactic Efficacy of Quercetin 3-β- O - d -Glucoside against Ebola Virus Infection

Qiu

Kroeker

et al. 2016

Antimicrob Agents Chemother

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Ebola outbreaks occur on a frequent basis, with the 2014-2015 outbreak in West Africa being the largest one ever recorded. This outbreak has resulted in over 11,000 deaths in four African countries and has received international attention and intervention. Although there are currently no approved therapies or vaccines, many promising candidates are undergoing clinical trials, and several have had success in promoting recovery from Ebola. However, these prophylactics and therapeutics have been designed and tested only against the same species of Ebola virus as the one causing the current outbreak. Future outbreaks involving other species would require reformulation and possibly redevelopment. Therefore, a broad-spectrum alternative is highly desirable. We have found that a flavonoid derivative called quercetin 3-␤-O-D-glucoside (Q3G) has the ability to protect mice from Ebola even when given as little as 30 min prior to infection. Furthermore, we have demonstrated that this compound targets the early steps of viral entry. Most promisingly, antiviral activity against two distinct species of Ebola virus was seen. This study serves as a proof of principle that Q3G has potential as a prophylactic against Ebola virus infection.

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“…The primary outcome (Box 1) was mortality within a period of 14 days. Doses in adults were determined based on results from mouse studies [30], as well as on pharmacokinetic simulation and dosage tests in humans [28]. …”

Section: Small Molecule Inhibitors: Direct Intracellular Inhibition Omentioning

confidence: 99%

Clinical Evaluation of Ebola Virus Disease Therapeutics

Liu

Wong

et al. 2017

Trends in Molecular Medicine

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Ebola virus disease (EVD) was first described over 40 years ago, but no treatment has been approved for humans. The 2013–2016 EVD outbreak in West Africa has expedited the clinical evaluation of several candidate therapeutics that act through different mechanisms, but with mixed results. Nevertheless, these studies are important because the accumulation of clinical data and valuable experience in conducting efficacy trials under emergency circumstances will lead to better implementation of similar studies in the future. Here, we summarize the results of EVD clinical trials, focus on the discussion of factors that may have potentially impeded the effectiveness of existing candidate therapeutics, and highlight considerations that may help meet the challenges ahead in the quest to develop clinically-approved drug(s).

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Ebola virus dynamics in mice treated with favipiravir

Cited by 60 publications

References 23 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

Prophylactic Efficacy of Quercetin 3-β- O - d -Glucoside against Ebola Virus Infection

Clinical Evaluation of Ebola Virus Disease Therapeutics

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