{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:51:11Z","timestamp":1790470271536,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T00:00:00Z","timestamp":1644796800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>This phase 1 postapproval study assessed the effect of the mitogen\u2010activated protein kinase kinase enzyme 1\/enzyme 2 inhibitor trametinib (2\u00a0mg once daily, repeat dosing) on the pharmacokinetics of combined oral contraceptives (COCs) containing norethindrone (NE; 1\u00a0mg daily) and ethinyl estradiol (EE; 0.035\u00a0mg daily) in 19 female patients with solid tumors. Compared with NE\/EE administered without trametinib, NE\/EE administered with steady\u2010state trametinib was associated with a clinically nonrelevant 20% increase in NE exposure (area under the curve [AUC]) and no effect on EE exposure (geometric mean ratio [geo\u2010mean] of NE\/EE\u00a0+\u00a0trametinib to NE\/EE [90%CI]: NE AUC calculated to the end of a dosing interval at steady\u2010state [AUC<jats:sub>tau<\/jats:sub>] 1.20 [1.02\u20101.41]; NE AUC from time zero to the last measurable concentration sampling time [AUC<jats:sub>last<\/jats:sub>] 1.2 [0.999\u20101.45]; EE AUC<jats:sub>tau<\/jats:sub> 1.06 [0.923\u20101.22]; EE AUC<jats:sub>last<\/jats:sub> 1.05 [0.883\u20101.25]). Maximum serum concentration (C<jats:sub>max<\/jats:sub>) of NE increased by 13% and C<jats:sub>max<\/jats:sub> of EE decreased by 8.5% when dosed with steady\u2010state trametinib compared with COCs administered alone (geo\u2010mean ratio [90%CI]: NE C<jats:sub>max<\/jats:sub> 1.13 [0.933\u20101.36]; EE C<jats:sub>max<\/jats:sub> 0.915 [0.803\u20101.04]). These results indicate that repeat\u2010dose trametinib does not lower exposure to NE or EE and, hence, is unlikely to impact the contraceptive efficacy of COCs. The pharmacokinetic parameters of trametinib and its metabolite M5 were consistent with historic data of trametinib alone. Coadministration of trametinib and COCs was generally well tolerated in this study, with observed safety signals consistent with the known safety profile of trametinib and no new reported safety events. Overall, the findings indicate that hormonal COCs can be coadministered in female patients who receive trametinib monotherapy without compromising the contraceptive efficacy.<\/jats:p>","DOI":"10.1002\/cpdd.1052","type":"journal-article","created":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T18:58:50Z","timestamp":1644865130000},"page":"585-596","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacokinetic Interaction Between the MEK1\/MEK2 Inhibitor Trametinib and Oral Contraceptives Containing Norethindrone and Ethinyl Estradiol in Female Patients With Solid Tumors"],"prefix":"10.1002","volume":"11","author":[{"given":"Hendrik\u2010Tobias","family":"Arkenau","sequence":"first","affiliation":[{"name":"Sarah Cannon Research Institute  London UK"},{"name":"Cancer Institute University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatienne","family":"Taylor","sequence":"additional","affiliation":[{"name":"CHU UCL Namur, Site Sainte\u2010Elisabeth  Namur Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Xu","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shripad","family":"Chitnis","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casilda","family":"Llacer\u2010Perez","sequence":"additional","affiliation":[{"name":"Hospital Clinico Universitario Virgen de la Victoria  Malaga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Moore","sequence":"additional","affiliation":[{"name":"Stephenson Cancer Centre University of Oklahoma  Oklahoma City Oklahoma USA"},{"name":"Sarah Cannon Research Institute  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanna Kumar","family":"Nidamarthy","sequence":"additional","affiliation":[{"name":"Novartis Healthcare Pvt. 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