Semi-Mechanistic Pharmacokinetic-Pharmacodynamic Model of Camostat Mesylate-Predicted Efficacy against SARS-CoV-2 in COVID-19

Abstract

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.

Keywords: COVID-19; antiviral pharmacology; camostat.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIG 1

The model schemes. (A) Biological model of targeting SARS CoV-2 cell entry through the TMPRSS2 inhibition. (B) Pharmacokinetic model for Camostat/FOY-251. Very fast transformation of Camostat mesylate into the active metabolite FOY-251 in physiological fluids is assumed. (C) Pharmacodynamic TMPRSS2 inhibition model (in vivo). The model considers TMPRSS2 synthesis (ksynt) and degradation rates (kdeg). TMPRSS2 inhibition by FOY-251 is considered as two-stage process: (i) 374 reversible binding (parameter Ki) of the drug, and (ii) the drug covalent binding to the target residue (kcat). The recovery of TMPRSS2 activity (with inactive metabolite [GBA] molecule release from active center) is described by parameter kdis (half-life of SPi state is about 14 h). For TMPRSS2 in vivo model ksynt was calculated based on kdeg value(assumed) and SP baseline level = 1.

FIG 2

FOY-251 Pharmacodynamic models fitted to the data of in vitro experiments of M. Hoffman et al. (18). (A) Recombinant TMPRSS2 activity (relative to control) versus FOY-251 concentration, incubation time 1 h. (B) Viral entry rate (relative to control) versus FOY-251 concentration, incubation time 2 h. (C) Viral entry rate dependence (from panel B) on the respective model predicted TMPRSS2 activity, incubation time 2 h. The model predictions are shown by solid lines with 90% CIs (gray-color filled bars), the data from in vitro experiments (digitized from [18]) are shown by black filled circles.

FIG 3

Predicted pharmacokinetic models, TMPRSS2 activity, and viral entry rate at different camostat doses. The PK model predictions (FOY-251 in plasma) are shown in the top panel by red solid lines with 90% CIs shown by filled bars. The predictions for TMPRSS2 activity (middle panel, green solid lines) and viral entry rate (bottom panel, blue solid lines) are shown with 90% CIs shown by filled bars. (A) camostat 200 mg q6h; (B) camostat 600 mg q6h; (C) camostat 600 mg q6h with two times slower.