{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:16:03Z","timestamp":1753892163525,"version":"3.41.2"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T00:00:00Z","timestamp":1714348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> TT-01025-CL is an oral, irreversible small molecule that potently inhibits vascular adhesion protein-1 (VAP-1) for the treatment of inflammation associated with non-alcoholic steatohepatitis (NASH). The objectives of this study were to evaluate the safety\/tolerability, pharmacokinetics, and pharmacodynamics of TT-01025-CL, a VAP-1 inhibitor, in healthy Chinese volunteers.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Double-blind, placebo-controlled, dose-escalation studies were conducted in subjects randomized to receive oral once-daily TT-01025-CL (ranges: 10\u2013300\u00a0mg [single dose]; 20\u2013100\u00a0mg for 7\u00a0days [multiple doses]) or placebo under fasting conditions. Safety and tolerability were monitored throughout the study. Pharmacokinetic (PK) parameters were determined using non-compartment analysis. The activity of semicarbazide-sensitive amine oxidase (SSAO)-specific amine oxidase and the accumulation of methylamine in plasma were evaluated as pharmacodynamic (PD) biomarkers.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> A total of 36 (single-dose group) and 24 (multiple-dose group) subjects were enrolled in the study. No serious adverse events (AEs) were reported, and no subject discontinued due to an AE. All treatment-emergent adverse events (TEAEs) were mild and moderate in intensity. No dose-dependent increase in the intensity or frequency of events was observed. TT-01025-CL was rapidly absorbed after administration. In the single-ascending dose (SAD) study, median T<jats:sub>max<\/jats:sub> ranged from 0.5 to 2\u00a0h and mean t<jats:sub>1\/2z<\/jats:sub> ranged from 2.09 to 4.39\u00a0h. PK was linear in the range of 100\u2013300\u00a0mg. The mean E<jats:sub>max<\/jats:sub> of methylamine ranged from 19.167 to 124.970\u00a0ng\/mL, with mean T<jats:sub>Emax<\/jats:sub> ranging from 13.5 to 28.0\u00a0h. The complete inhibition (&amp;gt;90%) of SSAO activity was observed at 0.25\u20130.5\u00a0h post-dose and was maintained 48\u2013168\u00a0h post-dose. In the multiple-ascending dose (MAD) study, a steady state was reached by day 5 in the 40\u00a0mg and 100\u00a0mg dose groups. Negligible accumulation was observed after repeated dosing. PK was linear in the range of 20\u2013100\u00a0mg. Plasma methylamine appeared to plateau at doses of 20\u00a0mg and above, with mean E<jats:sub>max<\/jats:sub> ranging from 124.142 to 156.070\u00a0ng\/mL and mean T<jats:sub>Emax<\/jats:sub> ranging from 14.2 to 22.0\u00a0h on day 7. SSAO activity in plasma was persistently inhibited throughout the treatment period. No evident change in methylamine and SSAO activity was observed in the placebo groups.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> TT-01025-CL was safe and well-tolerated at a single dose of up to 300\u00a0mg and multiple doses of up to 100\u00a0mg once daily for 7 consecutive days. Absorption and elimination occurred rapidly in healthy volunteers. Linearity in plasma exposure was observed. TT-01025-CL inhibited SSAO activity rapidly and persistently in humans. The profile of TT-01025-CL demonstrates its suitability for further clinical development.<\/jats:p>","DOI":"10.3389\/fphar.2024.1327008","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T04:38:17Z","timestamp":1714365497000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The first selective VAP-1 inhibitor in China, TT-01025-CL: safety, tolerability, pharmacokinetics, and pharmacodynamics of single- and multiple-ascending doses"],"prefix":"10.3389","volume":"15","author":[{"given":"Yuanxun","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zejuan","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuyi","family":"Weng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingsheng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shumao","family":"Ni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huimin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caixia","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"483135","DOI":"10.1155\/2012\/483135","article-title":"Nonalcoholic fatty liver disease and cardiovascular disease: has the time come for cardiologists to be hepatologists?","volume":"2012","author":"Ahmed","year":"2012","journal-title":"J. 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