{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T19:15:01Z","timestamp":1780514101758,"version":"3.54.1"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2023,7,2]],"date-time":"2023-07-02T00:00:00Z","timestamp":1688256000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,7,2]],"date-time":"2023-07-02T00:00:00Z","timestamp":1688256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Chemother Pharmacol"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Period 1: patients with locally advanced or metastatic solid tumors received \u2018cocktail\u2019: caffeine 200\u00a0mg, omeprazole 20\u00a0mg, and midazolam 2\u00a0mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225\u00a0mg twice daily on days 1\u20133 (five doses), with cocktail on day 3. After cocktail alone or in combination with adavosertib administration, 24-h pharmacokinetic sampling occurred for probe substrates and their respective metabolites paraxanthine, 5-hydroxyomeprazole (5-HO), and 1\u2032-hydroxymidazolam (1\u2032-HM). Safety was assessed throughout.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Of 33 patients (median age 60.0\u00a0years, range 41\u201383) receiving cocktail, 30 received adavosertib. Adavosertib co-administration increased caffeine, omeprazole, and midazolam exposure by 49%, 80%, and 55% (AUC<jats:sub>0\u201312<\/jats:sub>), respectively; AUC<jats:sub>0\u2013t<\/jats:sub> increased by 61%, 98%, and 55%. Maximum plasma drug concentration (C<jats:sub>max<\/jats:sub>) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1\u2032-HM exposure by 43% and 54% (AUC<jats:sub>0\u201312<\/jats:sub>) and 49% and 58% (AUC0\u2013t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased C<jats:sub>max<\/jats:sub> for paraxanthine and 5\u2013HO by 19% and 7%; C<jats:sub>max<\/jats:sub> increased by 33% for 1\u2032-HM. After receiving adavosertib, 19 (63%) patients had treatment-related adverse events (six [20%] grade\u2009\u2265\u20093).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Adavosertib (225\u00a0mg bid) is a weak inhibitor of CYP1A2, CYP2C19, and CYP3A.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>ClinicalTrials.gov<\/jats:title>\n                <jats:p>NCT03333824<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00280-023-04554-3","type":"journal-article","created":{"date-parts":[[2023,7,2]],"date-time":"2023-07-02T18:01:33Z","timestamp":1688320893000},"page":"193-203","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19, and CYP3A in patients with advanced solid tumors"],"prefix":"10.1007","volume":"92","clinical-trial-number":[{"clinical-trial-number":"nct03333824","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9643-1638","authenticated-orcid":false,"given":"Mats","family":"N\u00e5g\u00e5rd","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Lin","family":"Ah-See","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Strauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trisha","family":"Wise-Draper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard P.","family":"Safran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Nadeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Edenfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel D.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lone H.","family":"Ottesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh M.","family":"Mugundu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,2]]},"reference":[{"key":"4554_CR1","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1016\/0092-8674(87)90458-2","volume":"49","author":"P Russell","year":"1987","unstructured":"Russell P, Nurse P (1987) Negative regulation of mitosis by Wee1+, a gene encoding a protein kinase homolog. 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He also received, through an award to his institution, clinical trial funding for this study from AstraZeneca and other similar clinical trial funding support from the following sponsors: Bristol Myers Squibb, Bayer Pharmaceuticals, and AbbVie. WJE is a consultant for Chimerix Corp. MA and MN are employees and shareholders of AstraZeneca. LHO was an employee of AstraZeneca when this study was designed, executed, and reported. LHO is also a shareholder of AstraZeneca. All other authors have declared no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was performed in accordance with the ethical principles of the Declaration of Helsinki and is consistent with the International Council for Harmonisation\u2019s Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on bioethics [].","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The institutional review boards or independent ethics committees of all investigational sites approved the protocol, and all patients provided written, informed consent.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}]}}