tetano
Editor, Senior Moderator
Clin Transl Sci
. 2021 May 13.
doi: 10.1111/cts.13052. Online ahead of print.
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[SUP] 1 2 [/SUP], Hayato Arai[SUP] 1 [/SUP], Hiroyuki Iida[SUP] 1 [/SUP], Jiro Mukai[SUP] 1 [/SUP], Kenji Furukawa[SUP] 1 [/SUP], Seitaro Ohtsu[SUP] 3 [/SUP], Susumu Nakade[SUP] 1 [/SUP], Tomohiro Hikima[SUP] 2 [/SUP], Miwa Haranaka[SUP] 4 [/SUP], Naoto Uemura[SUP] 5 [/SUP]
Affiliations
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 four times daily under either of the following conditions: fasted state, after a meal, 30 minutes before a meal, or 1 hour 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 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 minutes before a meal was significantly lower; however, no significant difference was observed at 1 hour before a meal. The time above EC50 was 11.5 hours when camostat mesylate 600 mg was administered four times daily in the fasted state or 1 hour before a meal. Based on the results of this phase I study, we are currently conducting a phase III study.
Keywords: COVID-19; Camostat; GBPA; PPK; TMPRSS2 inhibitor; modeling and simulation.
. 2021 May 13.
doi: 10.1111/cts.13052. Online ahead of print.
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[SUP] 1 2 [/SUP], Hayato Arai[SUP] 1 [/SUP], Hiroyuki Iida[SUP] 1 [/SUP], Jiro Mukai[SUP] 1 [/SUP], Kenji Furukawa[SUP] 1 [/SUP], Seitaro Ohtsu[SUP] 3 [/SUP], Susumu Nakade[SUP] 1 [/SUP], Tomohiro Hikima[SUP] 2 [/SUP], Miwa Haranaka[SUP] 4 [/SUP], Naoto Uemura[SUP] 5 [/SUP]
Affiliations
- PMID: 33982445
- DOI: 10.1111/cts.13052
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 four times daily under either of the following conditions: fasted state, after a meal, 30 minutes before a meal, or 1 hour 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 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 minutes before a meal was significantly lower; however, no significant difference was observed at 1 hour before a meal. The time above EC50 was 11.5 hours when camostat mesylate 600 mg was administered four times daily in the fasted state or 1 hour before a meal. Based on the results of this phase I study, we are currently conducting a phase III study.
Keywords: COVID-19; Camostat; GBPA; PPK; TMPRSS2 inhibitor; modeling and simulation.