{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T14:50:06Z","timestamp":1747147806203,"version":"3.40.5"},"reference-count":27,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"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":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:p>The endothelin A receptor antagonist zibotentan, combined with the sodium\u2010glucose co\u2010transporter\u20102 inhibitor dapagliflozin, is being investigated for the treatment of chronic kidney disease with high proteinuria. To allow women of childbearing potential access to this treatment, highly effective contraception is required and drug interactions compromising contraception reliability must be avoided. This study investigated the risk of pharmacokinetic (PK) interaction between zibotentan and the contraceptives ethinyl estradiol and levonorgestrel. A single\u2010sequence, within\u2010participant comparison study was conducted in 24 healthy women of non\u2010childbearing potential, comparing the PK of ethinyl estradiol\/levonorgestrel alone and with zibotentan. Single oral doses of 0.06\u2009mg ethinyl estradiol\/0.3\u2009mg levonorgestrel were administered on Days 1 and 15; zibotentan 10\u2009mg was dosed orally, once\u2010daily through Days 6\u201319. PK profiles were determined and ethinyl estradiol\/levonorgestrel PK was compared between Day 1 and 15 based on geometric least\u2010squares mean ratios of PK parameters, including maximum observed concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) and area under the plasma concentration\u2013time curve from zero to infinity (AUC<jats:sub>inf<\/jats:sub>). Co\u2010administration with zibotentan did not affect ethinyl estradiol PK (geometric mean ratio [90% confidence interval] <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> 1.05 [0.99\u20131.11], AUC<jats:sub>inf<\/jats:sub> 1.00 [0.96\u20131.05]), while a weak interaction (increased exposure) was observed for levonorgestrel (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> 1.12 [1.02\u20131.23], AUC<jats:sub>inf<\/jats:sub> 1.30 [1.21\u20131.39]), which was regarded as without clinical relevance. Plasma exposure of ethinyl estradiol\/levonorgestrel was not reduced by multiple\u2010dose zibotentan. In conclusion, contraception containing ethinyl estradiol\/levonorgestrel is regarded possible under zibotentan\u2010containing treatments. This expands choices for women of childbearing potential, supporting diversity in the ZENITH High Proteinuria trial.<\/jats:p>","DOI":"10.1002\/cpt.3280","type":"journal-article","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T09:05:13Z","timestamp":1714467913000},"page":"372-379","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Zibotentan Can Be Co\u2010administered with Contraceptives Containing Ethinyl Estradiol and Levonorgestrel: A Pharmacokinetic Drug\u2013Drug Interaction Study"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0915-5070","authenticated-orcid":false,"given":"Anne\u2010Kristina","family":"Mercier","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abigail K.","family":"Kois","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&amp;D AstraZeneca  Gaithersburg Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9949-4193","authenticated-orcid":false,"given":"Deeyen","family":"Karsanji","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&amp;D AstraZeneca  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0525-1119","authenticated-orcid":false,"given":"Richard","family":"Baldry","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&amp;D AstraZeneca  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3496-2585","authenticated-orcid":false,"given":"Filip","family":"Birve","sequence":"additional","affiliation":[{"name":"Biometrics, Late\u2010Stage Development, Cardiovascular, Renal and Metabolism, R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Hedwall","sequence":"additional","affiliation":[{"name":"Clinical, Late\u2010Stage Development, Cardiovascular, Renal and Metabolism, R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3088-7647","authenticated-orcid":false,"given":"Oleksandr","family":"Molodetskyi","sequence":"additional","affiliation":[{"name":"Global Patient Safety BioPharmaceuticals, Chief Medical Office, R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Gillen","sequence":"additional","affiliation":[{"name":"Creek Lane PK, LLC  Waterford Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,4,30]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30045-3"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60595-4"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfad183"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)02230-4"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2015.06.048"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1552-6909.1998.tb02594.x"},{"key":"e_1_2_9_7_1","unstructured":"U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) & Center for Biologics Evaluation and Research (CBER).Enhancing the diversity of clinical trial populations\u2014eligibility criteria enrollment practices and trial designs guidance for industry<https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/enhancing\u2010diversity\u2010clinical\u2010trial\u2010populations\u2010eligibility\u2010criteria\u2010enrollment\u2010practices\u2010and\u2010trial> (2020) Accessed December 2023."},{"key":"e_1_2_9_8_1","unstructured":"United Nations Department of Economic and Social Affairs P.D.World Family Planning 2022: Meeting the changing needs for family planning: Contraceptive use by age and method<https:\/\/www.un.org\/development\/desa\/pd\/sites\/www.un.org.development.desa.pd\/files\/files\/documents\/2023\/Feb\/undesa_pd_2022_world\u2010family\u2010planning.pdf> (2022) Accessed December 2023."},{"key":"e_1_2_9_9_1","unstructured":"U.S. Department of Health and Human Services Food & Drug Administration & Center for Drug Evaluation and Research (CDER).Clinical drug interaction studies with combined oral contraceptives; 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