Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing

SARS-CoV-2 utilizes the IMP alpha/beta 1 heterodimer to enter host cell nuclei after gaining cellular access through the ACE2 receptor. Ivermectin has shown antiviral activity by inhibiting the formation of the importin-alpha (IMP alpha) and IMP alpha/beta 1 subunits as well as dissociating the IMP alpha/beta 1 heterodimer and has in vitro efficacy against SARS-CoV-2. Plasma and lung ivermectin concentrations vs. time profiles in cattle were used to determine the apparent plasma to lung tissue partition coefficient of ivermectin. This coefficient, together with a simulated geometric mean plasma profile of ivermectin from a published population pharmacokinetic model, was utilized to develop a minimal physiologically-based pharmacokinetic (mPBPK) model. The mPBPK model accurately described the simulated ivermectin plasma concentration profile in humans. The mPBPK model was also used to simulate human lung exposure to ivermectin after 12, 30, and 120 mg oral doses. The simulated ivermectin lung exposures reached a maximum concen-tration of 772 ng/mL, far less than the estimated 1750 ng/mL IC50 reported for ivermectin against SARS-CoV-2 in vitro. Further studies of ivermectin either reformulated for inhaled delivery or in combination with other antivirals with differing mechanisms of action is needed to assess its therapeutic potential. (C) 2020 Published by Elsevier Inc. on behalf of the American Pharmacists Association.