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Clinical Trial
. 2021 Sep;14(5):1967-1976.
doi: 10.1111/cts.13052. Epub 2021 Jun 2.

A phase I study of high dose camostat mesylate in healthy adults provides a rationale to repurpose the TMPRSS2 inhibitor for the treatment of COVID-19

Affiliations
Clinical Trial

A phase I study of high dose camostat mesylate in healthy adults provides a rationale to repurpose the TMPRSS2 inhibitor for the treatment of COVID-19

Junsaku Kitagawa et al. Clin Transl Sci. 2021 Sep.

Abstract

Camostat mesylate, an oral serine protease inhibitor, is used to treat chronic pancreatitis and reflux esophagitis. Recently, camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) were reported to inhibit the infection of cells by severe acute respiratory syndrome coronavirus 2 by inhibiting type II transmembrane serine protease. We conducted a phase I study to investigate high-dose camostat mesylate as a treatment for coronavirus disease 2019. Camostat mesylate was orally administered to healthy adults at 600 mg 4 times daily under either of the following conditions: fasted state, after a meal, 30 min before a meal, or 1 h before a meal, and the pharmacokinetics and safety profiles were evaluated. In addition, the time of plasma GBPA concentration exceeding the effective concentration was estimated as the time above half-maximal effective concentration (EC50 ) by using pharmacokinetic/pharmacodynamic modeling and simulation. Camostat mesylate was safe and tolerated at all dosages. Compared with the fasted state, the exposure of GBPA after a meal and 30 min before a meal was significantly lower; however, no significant difference was observed at 1 h before a meal. The time above EC50 was 11.5 h when camostat mesylate 600 mg was administered 4 times daily in the fasted state or 1 h before a meal. Based on the results of this phase I study, we are currently conducting a phase III study.

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Conflict of interest statement

J.K., H.I., H.A., J.M., K.F., S.O., and S.N. are employees of Ono Pharmaceutical Co., Ltd. T.H. is a consultant and N.U. is a paid consultant of Ono Pharmaceutical Co., Ltd. All other authors declare no competing interests for this work.

Figures

FIGURE 1
FIGURE 1
Study design of a phase I study in healthy subjects. Camostat mesylate 600 mg was administrated four times per day under the described conditions. PK, pharmacokinetic
FIGURE 2
FIGURE 2
GBPA concentration–time profiles in (a) cohort 1 and (b) cohort 2. Data are the arithmetic mean ± SD from the pharmacokinetic analysis set. In some samples, GBPA concentrations were below the lower limit of quantification (1.00 nmol/L). Broken lines represent EC50 of half‐maximal effective concentration. EC50, half‐maximal effective concentration; GBPA, 4‐(4‐guanidinobenzoyloxy)phenylacetic acid
FIGURE 3
FIGURE 3
Visual predictive check for the final GBPA population pharmacokinetic model. Shaded areas represent the 5th, 50th, and 95th percentiles of the observed data. Dashed lines represent the median value of the simulated data. Dot dash lines represent EC50 of GBPA. EC50, half‐maximal effective concentration; GBPA, 4‐(4‐guanidinobenzoyloxy)phenylacetic acid. (a) phase I single dose study, (b) phase I multiple dose study
FIGURE 4
FIGURE 4
The relationship between the daily dose and time above EC50 after the administration of camostat mesylate four times daily at 4‐h intervals under fasted conditions or at 1 h before a meal. The y‐axis represents the time above EC50, and the x‐axis represents the daily dose. The estimated value of the time above EC50 is plotted for each daily dose. The bold line represents the result of power model fitting. EC50, half‐maximal effective concentration

References

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