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Formulation, Stability, Pharmacokinetic, And Modeling Studies For Tests Of Synergistic Combinations Of Orally Available Approved Drugs Against Ebola Virus In Vivo

Courtney L. Finch, Julie Dyall, Shuang Xu, Elizabeth A. Nelson, Elena Postnikova, Janie Y. Liang, Huanying Zhou, Lisa Evans DeWald, Craig J. Thomas, Amy Wang, Xin Xu, Emma Hughes, Patrick J. Morris, Jon C. Mirsalis, Linh H. Nguyen, Maria P. Arolfo, Bryan Koci, Michael R. Holbrook, Lisa E. Hensley, Peter B. Jahrling, Connie Schmaljohn, Lisa M. Johansen, Gene G. Olinger, Joshua T. Schiffer, Judith M. White

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Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here, we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.