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A phase 1 drug\u2010drug interaction study was conducted to evaluate the effect of multiple\u2010dose administration of brigatinib on the single\u2010dose pharmacokinetics of midazolam, a sensitive cytochrome P450 3A substrate. In cycle 1, patients with <jats:italic>ALK<\/jats:italic>+ or <jats:italic>ROS1<\/jats:italic>+ solid tumors, including NSCLC, received a single 3\u2010mg dose of midazolam as an oral solution alone on day 1 and then coadministered with brigatinib on day 21 (brigatinib 90 mg once daily on days 2\u20108; 180 mg once daily on days 9\u201028). After cycle 1, patients could continue to receive brigatinib in 28\u2010day treatment cycles. The primary study objective was to characterize the effect of brigatinib 180 mg once daily on midazolam pharmacokinetics. The secondary objective was to assess safety. Exploratory efficacy endpoints included objective response rate and progression\u2010free survival. Brigatinib was generally well tolerated, and safety data were consistent with the known safety profile. Among the 10 patients with <jats:italic>ALK<\/jats:italic>+ NSCLC, the confirmed objective response rate was 30% and median progression\u2010free survival was 7.2 months. Coadministration of brigatinib reduced midazolam maximum observed plasma concentration by \u224816% (geometric least\u2010squares mean ratio, 0.836 [90%CI, 0.662\u20101.056]) and area under the plasma concentration\u2013time curve from time 0 to infinity by \u224826% (geometric least\u2010squares mean ratio, 0.741 [90%CI, 0.600\u20100.915]). Thus, brigatinib is a weak inducer of cytochrome P450 3A in vivo.<\/jats:p>","DOI":"10.1002\/jcph.2198","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T11:40:01Z","timestamp":1672314001000},"page":"583-592","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Phase 1 Drug\u2010Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam in Patients With <i>ALK\u2010<\/i>Positive or <i>ROS1<\/i>\u2010Positive Solid Tumors"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9266-2797","authenticated-orcid":false,"given":"Michael J.","family":"Hanley","sequence":"first","affiliation":[{"name":"Takeda Development Center Americas, Inc.  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