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Human liver microsomes\/recombinant CYP enzymes were evaluated in vitro. In vivo, a single\u2010center, open\u2010label, fixed\u2010sequence study was performed in healthy adults to explore the effect of 100\u2009mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50\u2009mg, CYP2C9), omeprazole (20\u2009mg, CYP2C19), midazolam (2\u2009mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24\u2009h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC<jats:sub>50<\/jats:sub> values of 8.6, 1.6, and 19\u201344\u2009\u03bcM, respectively, while showing a significant time\u2010dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single\u2010 (i.e., area under the plasma concentration\u2013time curve [AUC] ratio increased by 1.04\u2010, 2.05\u2010, and 1.56\u2010fold, respectively) and repeated\u2010dose (i.e., AUC ratio increased by 1.47\u2010, 6.84\u2010, and 3.71\u2010fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8\u2009days of 100\u2009mg b.i.d. administration. <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">Clinicaltrials.gov<\/jats:ext-link> ID: NCT05254548.<\/jats:p>","DOI":"10.1002\/prp2.1143","type":"journal-article","created":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T04:51:08Z","timestamp":1696654268000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Effect of nivasorexant (<scp>ACT<\/scp>\u2010539313), a selective orexin\u20101\u2010receptor antagonist, on multiple cytochrome <scp>P450<\/scp>\u00a0probe substrates in vitro and in vivo using a cocktail approach in healthy subjects"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7777-5734","authenticated-orcid":false,"given":"Benjamin","family":"Berger","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2415-3012","authenticated-orcid":false,"given":"Priska","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Berse","sequence":"additional","affiliation":[{"name":"CRS Berlin GmbH  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2380-2538","authenticated-orcid":false,"given":"Alexander","family":"Treiber","sequence":"additional","affiliation":[{"name":"Department of Preclinical Drug Metabolism and Pharmacokinetics Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Grignaschi","sequence":"additional","affiliation":[{"name":"Department of Preclinical Drug Metabolism and Pharmacokinetics Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-5817","authenticated-orcid":false,"given":"Jasper","family":"Dingemanse","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,6]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14251"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80949-6"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1054\/npep.2002.0892"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2015.04.012"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2014.00026"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2012.48"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881115615107"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2020.110166"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1588"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/73.5.658"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.3109\/00365528909091241"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-199003000-00010"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(96)00501-1"},{"key":"e_1_2_14_15_1","unstructured":"EMA. 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