The SARS-CoV-2 coronavirus, which causes
COVID-19, uses a viral surface spike
protein for host cell entry and the human cell-surface transmembrane
serine protease, TMPRSS2, to process the spike
protein.
Camostat mesylate, an orally available and clinically used
serine protease inhibitor, inhibits TMPRSS2, supporting clinical trials to investigate its use in
COVID-19. A one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for
camostat and the active metabolite
FOY-251 was developed, incorporating TMPRSS2 reversible covalent inhibition by
FOY-251, and empirical equations linking TMPRSS2 inhibition of SARS-CoV-2 cell entry. The model predicts that 95% inhibition of TMPRSS2 is required for 50% inhibition of viral entry efficiency. For
camostat 200 mg dosed four times daily, 90% inhibition of TMPRSS2 is predicted to occur but with only about 40% viral entry inhibition. For 3-fold higher
camostat dosing, marginal improvement of viral entry rate inhibition, up to 54%, is predicted. Because respiratory tract viral load may be associated with negative outcome, even modestly reducing viral entry and respiratory tract viral load may reduce
disease progression. This modeling also supports medicinal chemistry approaches to enhancing PK/PD and potency of the
camostat molecule. IMPORTANCE Strategies to repurpose already-approved drugs for the treatment of
COVID-19 has been attractive since the beginning of the pandemic.
Camostat mesylate, a
serine protease inhibitor approved in Japan for the treatment of acute exacerbations of
chronic pancreatitis, inhibits TMPRSS1, a host cell surface
serine protease essential for SARS-CoV-2 viral entry. In vitro experiments provided data suggesting that
camostat might be effective in the treatment of
COVID-19. Multiple clinical trials were planned to test the hypothesis that
camostat would be beneficial for treating
COVID-19 (for example, clinicaltrials.gov, NCT04353284). The present work used a one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) mathematical model for
camostat and the active metabolite
FOY-251, incorporating TMPRSS2 reversible covalent inhibition by
FOY-251, and empirical equations linking TMPRSS2 inhibition of SARS-CoV-2 cell entry. This work is valuable to guide further development of
camostat mesylate and possible medicinal chemistry derivatives for the treatment of
COVID-19.