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  • All the more reason to deprioritize the use of ivermectin in COVID-19.

    indeed we already know about some polymorphism affecting PK or cell entry or DDI so these are taken into account and are very important.

    In general, yes. If the impact has been previously incorporated in the PK analysis of the repurposed drugs, we’ll be able to use these knowledge in simulations

    Molecular docking studies help guide us to screen a huge database of compounds against molecular targets on SARS-CoV-2.

    If the an toxicity is related to exposure, then modeling can potentially be used to explore a shorter duration for the higher dose CQ.

    If the an toxicity is related to exposure, then modeling can potentially be used to explore a shorter duration for the higher dose CQ.

    This is a real-time effort, and simulations in silico are hand-in-glove with clinical trials. They play off of each other. Here, we show tools to help inform clinical trial design (which they are), and then we’ll move to take that clinical data to update our models. Learn-Confirm.

    There is clinical trial data emerging using bi or tri therapy. Indeed attacking the virus on multiple fronts might be advantageous. as the data accumulates our tools will use itA recent trial in Hong Kong showed that interferon+lopinavir+ritonavir+ribavirin was better than lopinavir+ritonavir alone. Yes, we think that polypharmacy is likely to be more effective. But, DDIs and synergistic safety issues call for caution.

    Those docking studies are “directional,” and we need to take the compounds screened there forward into relevant cell lines. Caco2, Vero6, etc.

    Most of the major repurposed drugs have some form of lung concentration predictions. Check the in silico workbench area of for lung simulations.

    We must absolutely correct for it. Our screening approaches check unbound fraction concentration relative to the reported IC50s, as the in vitro assays are typically performed in serum-free media. Critical consideration.

    Generally, these modeling efforts have undergone regulatory scrutiny when the compound is approved/licensed for the initial indication. So, we have very good information on what model is “best.”

    So far most of our knowledge are still obtained in vitro instead of in vivo. For C(t) at SOA we try to simulate using established popPK or PBPK models. We typically have in vitro concentrations (IC50) that inhibit viral replication in a test host cell system. Vero cell cultures are often used. The basic idea is to check to see if we can achieve concentrations in patients that approach that IC50.

    Indeed, this is very challenging. We have to make best use of our current knowledge and expert experience and integrate new learnings along the way as much and as fast as we can.

    We are currently developing viral kinetic simulations to address these, as well as combo drugs which usually bring multiple MoAs.

    What is the mechanism of action for hydroxychloroquine and azythromicin?

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