Ivermectin (IVM)

population PBPK/PD

Ivermectin is extensively used for 5 neglected tropical diseases at single oral doses of 150 to 200 μg/kg. The FDA has approved the drug for the treatment of intestinal strogyloidiasis and onchocerciasis. In Australia, the TGA has also approved ivermectin for the treatment of scabies at specified dosages.

Recently Caly et al. reported that "The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 *in vitro*". In this study, ivermectin was added to test tubes in which Vero-hSLAM cells were growing and found that ivermectin inhibited the replication SARS-CoV-2 in those cells, with an IC50 determined to be approximately 2 μM under these conditions.

The paper has generated widespread interest on medical and veterinary websites. The assumption is that, since the drug is FDA-approved, it would readily translate into a treatment or cure for COVID-19.

The question that was left unanswered by the research report was whether a single dose of 150 to 200 μg/kg could result in adequate amounts in a human body to inhibit replication of SARS-CoV-2 in the blood or the lungs.

The assumption that dosages used for safe and effective treatment of neglected tropical diseases could also lead to safe and efficacious concentrations over time in the potential cure of COVID-19 led to prompt responses from the scientific community (Bray 2020, Chaccour 2020, Momekov 2020). The prevailing opinion in the responses was that standard doses of ivermectin would not result in efficacious concentrations, and that extraordinary doses to achieve efficacious concentrations may result in unacceptable toxicity in COVID-19 patients.

Because of concerns about possible diversion of invermectin intended for use in animals, the US FDA issued a warning – that ivermectin in veterinary products should not be used for human therapy. In addition, the FDA reminded the public that ivermectin is not approved for the prevention or treatment of COVID-19.

The ivermectin simulations that follow help illustrate the time-concentration profiles following dosing of ivermectin in humans and how those concentrations compare to those needed for inhibition of replication in a test tube. The simulations do not take into account protein binding, whether the virus is intracellular or extracellular, or effects against the virus other than a direct inhibition of viral replication.