{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:22:46Z","timestamp":1784769766526,"version":"3.55.0"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,12,13]],"date-time":"2020-12-13T00:00:00Z","timestamp":1607817600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"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":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:p>Levonorgestrel (LNG) is the active moiety in many hormonal contraceptive formulations. It is typically coformulated with ethinyl estradiol (EE) to decrease intermenstrual bleeding. Due to its widespread use and CYP3A4\u2010mediated metabolism, there is concern regarding drug\u2010drug interactions (DDIs), particularly a suboptimal LNG exposure when co\u2010administered with CYP3A4 inducers, potentially leading to unintended pregnancies. The goal of this analysis was to determine the impact of DDIs on the systemic exposure of LNG. To this end, we developed and verified a physiologically\u2010based pharmacokinetic (PBPK) model for LNG in PK\u2010Sim (version 8.0) accounting for the impact of EE and body mass index (BMI) on LNG\u2019s binding to sex\u2010hormone binding globulin. Model parameters were optimized following intravenous and oral administration of 0.09\u00a0mg LNG. The combined LNG\u2010EE PBPK model was verified regarding CYP3A4\u2010mediated interaction by comparing to published clinical DDI study data with carbamazepine, rifampicin, and efavirenz (CYP3A4 inducers). Once verified, the model was applied to predict systemic LNG exposure in normal BMI and obese women (BMI\u00a0\u2265\u00a030\u00a0kg\/m<jats:sup>2<\/jats:sup>) with and without co\u2010administration of itraconazole (competitive CYP3A4 inhibitor) and clarithromycin (mechanism\u2010based CYP3A4 inhibitor). Total and free LNG exposures, when co\u2010administered with EE, decreased 2\u2010fold in the presence of rifampin, whereas they increased 1.5\u2010fold in the presence of itraconazole. Although changes in total and unbound exposure were decreased in obese women compared with normal BMI women, the relative impact of DDIs on LNG exposure was similar between both groups.<\/jats:p>","DOI":"10.1002\/psp4.12572","type":"journal-article","created":{"date-parts":[[2020,11,21]],"date-time":"2020-11-21T01:52:57Z","timestamp":1605923577000},"page":"48-58","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug\u2010Drug Interactions Using Physiologically Based Pharmacokinetic Modeling"],"prefix":"10.1002","volume":"10","author":[{"given":"Brian","family":"Cicali","sequence":"first","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Lingineni","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Cristofoletti","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Wendl","sequence":"additional","affiliation":[{"name":"Bayer AG Pharmaceuticals Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Hoechel","sequence":"additional","affiliation":[{"name":"Bayer AG Pharmaceuticals Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"Wiesinger","sequence":"additional","affiliation":[{"name":"Bayer AG Pharmaceuticals Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayyappa","family":"Chaturvedula","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy System College of Pharmacy University of Northern Texas Health Science Center Fort Worth Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valvanera","family":"Vozmediano","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12,13]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.4137\/CMRH.S5030"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.26015"},{"key":"e_1_2_10_3_1","first-page":"235","article-title":"The lowest\u2010dose, extended\u2010cycle combined oral contraceptive pill with continuous ethinyl estradiol in the United States: a review of the literature on ethinyl estradiol 20 \u03bcg\/levonorgestrel 100 \u03bcg + ethinyl estradiol 10 \u03bcg","volume":"2","author":"Krishnan S.","year":"2010","journal-title":"Int. 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