**6. Pharmacokinetics and dose considerations for ivermectin as cancer therapy**

Due to its relatively long history of extensive use, the pharmacokinetics of ivermectin has been well studied. The oral route is the only approved for ivermectin administration in humans although it can be given subcutaneously and the intravenous route of administration has also been investigated. Ivermectin is a fat-soluble compound and reaches a peak concentration 4-5 hours after oral administration, and it has a half-life of approximately 19 hours. After administration, it is subsequently extensively metabolized in human liver microsomes by cytochrome P-4503A4, converting the drug to at least ten metabolites, most of them hydroxylated and demethylated derivatives. Its excretion is mainly by the fecal route, and only 1% is excreted in the urine [49]. In healthy individuals and patients infected with onchocerciasis treated with a dose of 0.150 mg /Kg of Ivermectin, significant variability in pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion is not observed [49].

The therapeutic dose for ivermectin as an anti-parasitic compound for human use is is between 0.1 and 0.4 mg/ Kg [4–7], resulting in an AUC of 1,444 μg/h/ mL. This drug exposure, which translates to a plasma concentration of 1.65 μM, is however less than concentrations of 5 μM or greater that has been found necessary to inhibit tumor cells *in vitro* In a phase I pharmacokinetic study done in healthy volunteers, it was demonstrated that doses up to 2 mg/Kg which leads to an AUC of 4,547 μg/h/mL can translate into a plasma concentration of 5 μM [50], thus the recommended dose for cancer therapy should likely be 2 mg/kg or higher.
