{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T01:22:18Z","timestamp":1773019338425,"version":"3.50.1"},"reference-count":26,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T00:00:00Z","timestamp":1636329600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1185454"],"award-info":[{"award-number":["OPP1185454"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:p>Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g., levonorgestrel (LNG)) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug\u2010drug interactions (DDIs) and obesity (women with body mass index (BMI)\u00a0\u2265\u00a030\u00a0kg\/m<jats:sup>2<\/jats:sup>) are prime suspects for decreased LNG efficacy. Therefore, we developed an integrated physiologically\u2010based pharmacokinetic modeling and model\u2010based meta\u2010analysis approach to determine LNG\u2019s efficacy threshold concentrations and to evaluate the impact of DDIs and obesity on the efficacy of LNG\u2010containing hormonal contraceptives (HCs). Based on this approach, co\u2010administration of strong CYP3A4 inducers and LNG\u2010containing HCs (LNG150: LNG 150\u00a0\u00b5g\u00a0+\u00a0EE 30\u00a0\u00b5g and LNG100: LNG 100\u00a0\u00b5g\u00a0+\u00a0EE 20\u00a0\u00b5g) resulted in a predicted clinically relevant decrease of LNG plasma exposure (women with BMI\u00a0&lt;\u00a025\u00a0kg\/m<jats:sup>2<\/jats:sup>: 50\u201365%; obese women: 70\u201375%). Following administration of LNG150 or LNG100 in the presence of a CYP3A4 inducer, there was an increase in mean Pearl Index of 1.2\u20131.30 and 1.80\u20132.10, respectively, in women with BMI\u00a0&lt;\u00a025\u00a0kg\/m<jats:sup>2<\/jats:sup> (incidence rate ratios (IRRs): 1.7\u20132.2), whereas it ranged from 1.6\u20131.80 and 2.40\u20132.85 in obese women (IRR: 2.2\u20133.0), respectively. Our results suggest that the use of backup or alternate methods of contraception is not necessarily required for oral LNG\u00a0+\u00a0EE formulations except within circumstances of both obesity and strong CYP3A4 inducer concomitance following administration of LNG100.<\/jats:p>","DOI":"10.1002\/cpt.2457","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T14:55:33Z","timestamp":1634828133000},"page":"509-518","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Determining the Exposure Threshold for Levonorgestrel Efficacy Using an Integrated Model Based Meta\u2010Analysis Approach"],"prefix":"10.1111","volume":"111","author":[{"given":"Karthik","family":"Lingineni","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayyappa","family":"Chaturvedula","sequence":"additional","affiliation":[{"name":"The University of North Texas Health Science Center Fort Worth Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Cicali","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo","family":"Cristofoletti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Wendl","sequence":"additional","affiliation":[{"name":"Bayer AG Leverkusen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joachim","family":"Hoechel","sequence":"additional","affiliation":[{"name":"Bayer AG Leverkusen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua D.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Outcomes &amp; Policy Center for Drug Evaluation &amp; Safety College of Pharmacy University of Florida Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valvanera","family":"Vozmediano","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Nations U.Department of Economic and Social Affairs Population Division (2019). Contraceptive Use by Method 2019: Data Booklet (ST\/ESA\/SER.A\/435)."},{"key":"e_1_2_10_3_1","volume-title":"Current Contraceptive Status Among Women Aged 15\u201344: United States, 2011\u20132013","author":"Daniels K.","year":"2014"},{"key":"e_1_2_10_4_1","volume-title":"Current Contraceptive Status Among Women Aged 15\u201349: United States, 2015\u20132017","author":"Daniels K.","year":"2018"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1285"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12357"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110855"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2013.04.001"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0033-1363965"},{"key":"e_1_2_10_10_1","volume-title":"Labeling for Combined Hormonal Contraceptives: Guidance for Industry (Draft Guidance)","author":"Center For Drug Evaluation and Research, Food and Drug Administration","year":"2017"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12499"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12572"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/13697130500148875"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2012.122"},{"key":"e_1_2_10_15_1","unstructured":"Electronic medicines compendium Norgestron SmPC<https:\/\/www.medicines.org.uk\/emc\/medicine\/1834>."},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.maturitas.2003.09.014"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2018.1536544"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2020.12.002"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2016.03.010"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-198325060-00003"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3109\/07853899309164160"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000000177"},{"key":"e_1_2_10_23_1","first-page":"CD008452","article-title":"Hormonal contraceptives for contraception in overweight or obese women","volume":"8","author":"Lopez L.M.","year":"2016","journal-title":"Cochrane Database Syst Rev."},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2015.07.016"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(90)90039-X"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4731(90)90291-Y"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(94)90014-0"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2457","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.2457","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2457","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:30:53Z","timestamp":1699363853000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.2457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,8]]},"references-count":26,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["10.1002\/cpt.2457"],"URL":"https:\/\/doi.org\/10.1002\/cpt.2457","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,8]]},"assertion":[{"value":"2021-06-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}