The theory that ivermectin’s anti-viral activity is dependent on unachievable tissue concentrations is incorrect as follows:
In the cell culture study by Caly et al from Monash University in Australia, although very high concentrations of ivermectin were used, this was not a human model. Humans have immune and circulatory systems working in concert with ivermectin, thus concentration required in humans have little relation to concentrations used in a laboratory cell culture. Further, prolonged durations of exposure to a drug likely would require a fraction of the dosing in a short-term cell model exposure.
There are multiple mechanisms by which ivermectin is thought to exert its anti-viral effects, with the least likely mechanism that of the blocking of importins as theorized in the Monash study above. These other mechanisms are not thought to require either supraphysiologic doses or concentrations and include
competitive binding of ivermectin with the host receptor-binding region of SARS-CoV-2 spike protein, limiting binding to the ACE-2 receptor;
binding to the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), thereby inhibiting viral replication (Swargiary, 2020);
binding/interference with multiple essential structural and non-structural proteins required by the virus in order to replicate.
The theory that ivermectin would need supraphysiologic tissue concentration to be effective is most strongly disproven by the now 24 controlled clinical trials which used standard doses of ivermectin yet reported large clinical impacts in reducing rates of transmission, deterioration, and mortality.
In the cell culture study by Caly et al from Monash University in Australia, although very high concentrations of ivermectin were used, this was not a human model. Humans have immune and circulatory systems working in concert with ivermectin, thus concentration required in humans have little relation to concentrations used in a laboratory cell culture. Further, prolonged durations of exposure to a drug likely would require a fraction of the dosing in a short-term cell model exposure. There are multiple mechanisms by which ivermectin is thought to exert its anti-viral effects, with the least likely mechanism that of the blocking of importins as theorized in the Monash study above. These other mechanisms are not thought to require either supraphysiologic doses or concentrations and include competitive binding of ivermectin with the host receptor-binding region of SARS-CoV-2 spike protein, limiting binding to the ACE-2 receptor; binding to the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), thereby inhibiting viral replication (Swargiary, 2020); binding/interference with multiple essential structural and non-structural proteins required by the virus in order to replicate. The theory that ivermectin would need supraphysiologic tissue concentration to be effective is most strongly disproven by the now 24 controlled clinical trials which used standard doses of ivermectin yet reported large clinical impacts in reducing rates of transmission, deterioration, and mortality.