{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:49:08Z","timestamp":1768438148825,"version":"3.49.0"},"reference-count":12,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:00:00Z","timestamp":1614643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:p>Bruton\u2019s tyrosine kinase (BTK) is a target for treatment of hematologic malignancies and autoimmune diseases. TAK\u2010020 is a highly selective covalent BTK inhibitor that inhibits both B cell receptor and fragment crystallizable receptor signaling. We assessed the safety\/tolerability and pharmacokinetics\/pharmacodynamics (PDs) of TAK\u2010020 in healthy subjects. Each cohort of the single\u2010rising dose (<jats:italic>n<\/jats:italic>\u00a0=\u00a072; 9 cohorts) and the multiple\u2010rising dose (<jats:italic>n<\/jats:italic>\u00a0=\u00a048; 6 cohorts) portions of the study comprised six TAK\u2010020\u2010treated and two placebo\u2010treated, subjects aged 18\u201355\u00a0years (inclusive). The PD effects were assessed by measuring BTK occupancy and the inhibition of fragment crystallizable epsilon receptor 1 (Fc\u03b5RI)\u2010mediated activation of basophils. Overall, treatment\u2010emergent adverse events (TEAEs) were similar to placebo; there were no serious TEAEs or no TEAEs leading to discontinuation. TAK\u2010020 was rapidly absorbed (median time to maximum plasma concentration (T<jats:sub>max<\/jats:sub>) 45\u201360\u00a0minutes) with a half\u2010life of ~\u00a03\u20139\u00a0hours at doses \u2265\u00a02.5\u00a0mg. TAK\u2010020 exposure was generally dose proportional for single doses \u2264\u00a070\u00a0mg and after multiple doses of \u2264\u00a060\u00a0mg once daily. Target occupancy was dose dependent, with doses \u2265\u00a02.5\u00a0mg yielding maximum and sustained occupancy &gt;\u00a070% for &gt;\u00a096\u00a0hours. Single doses \u2265\u00a04.4\u00a0mg reduced Fc\u03b5RI\u2010mediated activation of basophils by &gt;\u00a080% and comparable inhibition was observed with daily dosing \u22653.75\u00a0mg for 9\u00a0days. Inhibition persisted for 24\u201372\u00a0hours postdose and the duration generally increased with dose. TAK\u2010020 was generally well\u2010tolerated in healthy subjects after single and multiple doses and demonstrated target engagement and pathway modulation. The PD effects outlasted drug exposures, as expected for covalent inhibition of BTK.<\/jats:p>","DOI":"10.1111\/cts.12871","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T13:54:01Z","timestamp":1614693241000},"page":"820-828","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Phase I, Randomized, Double\u2010Blind, Placebo\u2010Controlled, Single\u2010Dose and Multiple\u2010Rising\u2010Dose Study of the BTK Inhibitor TAK\u2010020 in Healthy Subjects"],"prefix":"10.1111","volume":"14","author":[{"given":"Ehsanollah","family":"Esfandiari","sequence":"first","affiliation":[{"name":"Takeda Pharmaceuticals International Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Chen","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals International Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glennda","family":"Smithson","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals International Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derek","family":"Blair","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals International Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helene","family":"Faessel","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals International Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Wagner","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals International Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lachy","family":"Mclean","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals International Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5503-7172","authenticated-orcid":false,"given":"Eric R.","family":"Fedyk","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals International Inc. Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,3,2]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.65.3.286"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0039OC"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300125"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400666"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3400"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-015-0201-1"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1901981"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12713"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11882-012-0324-x"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.42.7906"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.794"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.10.042"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.12871","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.12871","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.12871","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T03:09:47Z","timestamp":1693364987000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.12871"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,2]]},"references-count":12,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1111\/cts.12871"],"URL":"https:\/\/doi.org\/10.1111\/cts.12871","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,2]]},"assertion":[{"value":"2020-06-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}