{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:43:29Z","timestamp":1790671409500,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,4,27]],"date-time":"2018-04-27T00:00:00Z","timestamp":1524787200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:p>Current formulations of combined oral contraceptives (COC) containing ethinylestradiol (EE) have \u226435 \u03bcg due to increased risks of cardiovascular diseases (CVD) with higher doses of EE. Low\u2010dose formulations however, have resulted in increased incidences of breakthrough bleeding and contraceptive failure, particularly when coadministered with inducers of cytochrome P450 enzymes (CYP). The developed physiologically based pharmacokinetic model quantitatively predicted the effect of CYP3A4 inhibition and induction on the pharmacokinetics of EE. The predicted C<jats:sub>max<\/jats:sub> and AUC ratios when coadministered with voriconazole, fluconazole, rifampicin, and carbamazepine were within 1.25 of the observed data. Based on published clinical data, an AUC<jats:sub>ss<\/jats:sub> value of 1,000 pg\/ml.h was selected as the threshold for breakthrough bleeding. Prospective application of the model in simulations of different doses of EE (20 \u03bcg, 35 \u03bcg, and 50 \u03bcg) identified percentages of the population at risk of breakthrough bleeding alone and with varying degrees of CYP modulation.<\/jats:p>","DOI":"10.1002\/cpt.1085","type":"journal-article","created":{"date-parts":[[2018,4,11]],"date-time":"2018-04-11T03:25:52Z","timestamp":1523417152000},"page":"1229-1239","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Risk\u2013Benefit Assessment of Ethinylestradiol Using a Physiologically Based Pharmacokinetic Modeling Approach"],"prefix":"10.1111","volume":"104","author":[{"given":"Udoamaka","family":"Ezuruike","sequence":"first","affiliation":[{"name":"Simcyp Limited (a Certara company) Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Humphries","sequence":"additional","affiliation":[{"name":"Simcyp Limited (a Certara company) Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Dickins","sequence":"additional","affiliation":[{"name":"Simcyp Limited (a Certara company) Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8809-1960","authenticated-orcid":false,"given":"Sibylle","family":"Neuhoff","sequence":"additional","affiliation":[{"name":"Simcyp Limited (a Certara company) Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain","family":"Gardner","sequence":"additional","affiliation":[{"name":"Simcyp Limited (a Certara company) Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Rowland Yeo","sequence":"additional","affiliation":[{"name":"Simcyp Limited (a Certara company) Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,4,27]]},"reference":[{"key":"e_1_2_9_1_1","unstructured":"Smyth C.Contraception Failure Blamed for Abortions. <https:\/\/www.thetimes.co.uk\/article\/contraception-failure-blamed-for-abortions-w8ddnm5qz> (2017). Accessed 7 July 2017."},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-128-6-199803150-00008"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.09.042"},{"key":"e_1_2_9_4_1","unstructured":"U.S. Food & Drug Administration.Labeling for Combined Hormonal Contraceptives: Guidance for Industry. <https:\/\/www.fda.gov\/ucm\/groups\/fdagov-public\/@fdagov-drugs-gen\/documents\/document\/ucm590673.pdf> (2017). Accessed 1 December 2017."},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2012.12.011"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/009127009803801109"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200746020-00003"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.0550351"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0039-128X(76)90144-6"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(85)90105-2"},{"key":"e_1_2_9_11_1","unstructured":"Department of Pharmaceutics & University of Washington.Drug Interaction Database Program. <https:\/\/www.druginteractioninfo.org\/> Accessed 1 August 2017."},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12745"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.539"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(79)90098-2"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1982.tb01382.x"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1981.tb00534.x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920007782109733"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(91)90069-R"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(87)90095-3"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0010-7824(96)00194-1"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002280050098"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.27.1900"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.104.000182"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-014-1711-0"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2011.08.012"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.55602.x"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2007.03084.x"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0029-7844(01)01443-0"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(99)70138-4"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2004.11.004"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02917.x"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1177\/00912709922007985"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2002.121217"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270011419855"},{"key":"e_1_2_9_35_1","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1177\/135965350801300415","article-title":"Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low\u2010dose ritonavir in healthy women","volume":"13","author":"Sekar V.J.","year":"2008","journal-title":"Antivir. Ther"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1999.tb00779.x"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.1999.00081.x"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.20058"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.30.7.795"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.2133\/dmpk.24.53"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(79)90036-2"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm9810102"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2009.12.002"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.115.066845"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1022210801734"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4731(90)90290-9"},{"key":"e_1_2_9_47_1","first-page":"362","article-title":"Plasma protein binding of ethinyloestradiol: effect of disease and interaction with drugs","volume":"27","author":"Pacifici G.M.","year":"1989","journal-title":"Int. J. Clin. Pharmacol. Ther. Toxicol"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(98)80016-1"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1177\/00912700122010456"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(95)00252-9"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcpt.1085","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.1085","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:28:47Z","timestamp":1699363727000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.1085"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,27]]},"references-count":50,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018,12]]}},"alternative-id":["10.1002\/cpt.1085"],"URL":"https:\/\/doi.org\/10.1002\/cpt.1085","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,27]]},"assertion":[{"value":"2017-11-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-03-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-04-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}