{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T02:45:13Z","timestamp":1777430713423,"version":"3.51.4"},"reference-count":24,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2017,9,20]],"date-time":"2017-09-20T00:00:00Z","timestamp":1505865600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Cathepsin C (CTSC) is necessary for the activation of several serine proteases including neutrophil elastase (NE), cathepsin G and proteinase 3. GSK2793660 is an oral, irreversible inhibitor of CTSC that is hypothesized to provide an alternative route to achieve NE inhibition and was tested in a Phase I study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Single escalating oral doses of GSK2793660 from 0.5 to 20\u00a0mg or placebo were administered in a randomized crossover design to healthy male subjects; a separate cohort received once daily doses of 12\u00a0mg or placebo for 21\u00a0days. Data were collected on safety, pharmacokinetics, CTSC enzyme inhibition and blood biomarkers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Single, oral doses of GSK2793660 were able to dose\u2010dependently inhibit whole blood CTSC activity. Once daily dosing of 12\u00a0mg GSK2793660 for 21\u00a0days achieved \u226590% inhibition (95% CI: 56, 130) of CTSC within 3\u00a0h on day 1. Only modest reductions of whole blood enzyme activity of approximately 20% were observed for NE, cathepsin G and proteinase 3. Seven of 10 subjects receiving repeat doses of GSK2793660 manifested epidermal desquamation on palmar and plantar surfaces beginning 7\u201310\u00a0days after dosing commencement. There were no other clinically important safety findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>GSK2793660 inhibited CTSC activity but not the activity of downstream neutrophil serine proteases. The palmar\u2013plantar epidermal desquamation suggests a previously unidentified role for CTSC or one of its target proteins in the maintenance and integrity of the epidermis at these sites, with some similarities to the phenotype of CTSC\u2010deficient humans.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13398","type":"journal-article","created":{"date-parts":[[2017,8,11]],"date-time":"2017-08-11T19:56:35Z","timestamp":1502481395000},"page":"2813-2820","source":"Crossref","is-referenced-by-count":54,"title":["Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660)"],"prefix":"10.1111","volume":"83","author":[{"given":"Bruce E.","family":"Miller","sequence":"first","affiliation":[{"name":"Respiratory Therapy Area Unit GSK R&amp;D  King of Prussia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth J.","family":"Mayer","sequence":"additional","affiliation":[{"name":"Respiratory Therapy Area Unit GSK R&amp;D  King of Prussia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Navin","family":"Goyal","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Modeling and Simulation GSK R&amp;D  King of Prussia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne","family":"Bal","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Sciences and Study Operations GSK R&amp;D  Stockley Park UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nigel","family":"Dallow","sequence":"additional","affiliation":[{"name":"Clinical Statistics GSK R&amp;D  Stockley Park UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malcolm","family":"Boyce","sequence":"additional","affiliation":[{"name":"Hammersmith Medicines Research, Cumberland Avenue  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Respiratory Therapy Area Unit GSK R&amp;D  King of Prussia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"Churchill","sequence":"additional","affiliation":[{"name":"Hammersmith Medicines Research, Cumberland Avenue  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Heslop","sequence":"additional","affiliation":[{"name":"Department of In vitro\/In vivo Translation GlaxoSmithKline  Ware UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7212-6401","authenticated-orcid":false,"given":"Aili L.","family":"Lazaar","sequence":"additional","affiliation":[{"name":"Respiratory Therapy Area Unit GSK R&amp;D  King of Prussia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,9,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.108.045682"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.12.7277"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.37.2.88"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301293"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.61"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI76009"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10314"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/70525"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00278288"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.002733"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0000000000000001"},{"key":"e_1_2_9_13_1","unstructured":"FDA.2002.Guidance for industry food effect bioavailability and fed bioequivalence studies Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2002. 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