{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T12:48:51Z","timestamp":1754484531303,"version":"3.41.2"},"reference-count":8,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T00:00:00Z","timestamp":1727827200000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad\u2010spectrum anti\u2010inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART\u2010648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases. According to the estimated clinical doses based on an in\u00a0vitro whole\u2010blood assay, a phase I study was designed. The purpose of this phase I study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following single and multiple administration of ART\u2010648 in healthy subjects. PD was assessed by suppression of lipopolysaccharide\u2010induced TNF\u03b1 release in ex\u00a0vivo whole\u2010blood assay. In the single rising dose study, ART\u2010648 was safe and well tolerated with a dose\u2010proportional increase in exposures up to 4\u2009mg. Single doses of ART\u2010648 demonstrated dose\u2010dependent PD response, indicating target engagement at 2\u20108 mg doses. In the multiple rising dose study, doses up to 4\u2009mg BID after careful titration were well tolerated, while doses up to 6\u2009mg BID were tolerated not in all but the majority of subjects. In conclusion, ART\u2010648 exhibits a favorable PK profile with robust target engagement at clinically safe and tolerated doses identified in healthy subjects.<\/jats:p>","DOI":"10.1111\/cts.70024","type":"journal-article","created":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T11:39:31Z","timestamp":1727869171000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Safety, pharmacokinetics, and pharmacodynamics of <scp>ART<\/scp>\u2010648, a <scp>PDE4<\/scp> inhibitor in healthy subjects: A randomized, placebo\u2010controlled phase I study"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9821-3325","authenticated-orcid":false,"given":"Akira","family":"Tanaka","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine Oita University  Oita Japan"},{"name":"ARTham Therapeutics Inc.  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Nagabukuro","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine Oita University  Oita Japan"},{"name":"ARTham Therapeutics Inc.  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4466-0145","authenticated-orcid":false,"given":"Kanako","family":"Kuniyeda","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine Oita University  Oita Japan"},{"name":"ARTham Therapeutics Inc.  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6183-2674","authenticated-orcid":false,"given":"Haruhi","family":"Ando","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine Oita University  Oita Japan"},{"name":"ARTham Therapeutics Inc.  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshinori","family":"Higashi","sequence":"additional","affiliation":[{"name":"CTD Inc.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5717-8251","authenticated-orcid":false,"given":"Hirokazu","family":"Wakuda","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine Oita University  Oita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0127-2118","authenticated-orcid":false,"given":"Naoyuki","family":"Otani","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine Oita University  Oita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8920-1447","authenticated-orcid":false,"given":"Hideo","family":"Kudo","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine Oita University  Oita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masae","family":"Kuranari","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine Oita University  Oita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8256-0516","authenticated-orcid":false,"given":"Hidetoshi","family":"Furuie","sequence":"additional","affiliation":[{"name":"Medical Corporation Heishinkai OPHAC Hospital  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3722-8979","authenticated-orcid":false,"given":"Naoto","family":"Uemura","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine Oita University  Oita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,10,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-11-96"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/FPHAR.2018.01048"},{"key":"e_1_2_10_4_1","unstructured":"Celgene. 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