{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:18:02Z","timestamp":1778865482801,"version":"3.51.4"},"reference-count":16,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,11,17]],"date-time":"2024-11-17T00:00:00Z","timestamp":1731801600000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV\u2010010213"],"award-info":[{"award-number":["INV\u2010010213"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"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":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Breakthrough bleeding (BTB) is a common side effect of hormonal contraception and is thought to impact adherence to combined oral contraceptives (COCs) but respective dose\u2013response relationships are not yet fully understood. Therefore, the objective of this model\u2010based meta\u2010analysis (MBMA) was to establish dose\u2013response for COCs containing different progestin\/EE combinations using BTB as the pharmacodynamic endpoint. Data from 25 studies containing BTB information of 4 progestins (desogestrel, drospirenone, gestodene, and levonorgestrel) in combination with ethinyl estradiol (EE) at various dose levels was used for this analysis. The results of our MBMA show that BTB is significantly increased upon initiation of COC use but subsides over time. The time needed for BTB to return to baseline depends on the EE dose and differs marginally between progestins during the initial months of use at the same EE dose. BTB typically returns to baseline within 3\u2009months at the highest (30\u2009\u03bcg) dose, whereas it can take significantly longer to reestablish a regular bleeding pattern at lower EE doses (15 and 20\u2009\u03bcg), irrespective of the progestin used. The dose\u2013response relationships established for BTB across different progestin\/EE combinations can now be used to support the selection of optimal COC dosing\/treatment regimens and serve as the scientific basis for evaluating the impact of clinically relevant factors, including drug\u2013drug interactions and demographics, on BTB.<\/jats:p>","DOI":"10.1002\/psp4.13261","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T04:40:59Z","timestamp":1731904859000},"page":"2016-2025","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Development of breakthrough bleeding model of combined\u2010oral contraceptives utilizing model\u2010based meta\u2010analysis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2233-727X","authenticated-orcid":false,"given":"Huili","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Center for Pharmacometrics and Systems Pharmacology University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dain","family":"Chun","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Center for Pharmacometrics and Systems Pharmacology University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1272-8093","authenticated-orcid":false,"given":"Karthik","family":"Lingineni","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Center for Pharmacometrics and Systems Pharmacology University of Florida  Orlando Florida USA"},{"name":"Novartis Pharmaceutical Corporation  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6342-9611","authenticated-orcid":false,"given":"Serge","family":"Guzy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Center for Pharmacometrics and Systems Pharmacology University of Florida  Orlando Florida USA"},{"name":"Pop\u2010Pharm Pharmacometrics Service  Albany California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2619-0343","authenticated-orcid":false,"given":"Rodrigo","family":"Cristofoletti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Center for Pharmacometrics and Systems Pharmacology University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joachim","family":"Hoechel","sequence":"additional","affiliation":[{"name":"Bayer AG  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2608-616X","authenticated-orcid":false,"given":"Tianze","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Outcomes and Policy, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7932-8599","authenticated-orcid":false,"given":"Brian","family":"Cicali","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Center for Pharmacometrics and Systems Pharmacology University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2636-1889","authenticated-orcid":false,"given":"Valvanera","family":"Vozmediano","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Center for Pharmacometrics and Systems Pharmacology University of Florida  Orlando Florida USA"},{"name":"Model Informed Development CTI Laboratories  Covington Kentucky USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4998-1167","authenticated-orcid":false,"given":"Stephan","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Center for Pharmacometrics and Systems Pharmacology University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,11,17]]},"reference":[{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9378(99)70718-0"},{"issue":"5","key":"e_1_2_10_4_1","first-page":"355","article-title":"Unintended pregnancies and use, misuse and discontinuation of oral contraceptives","volume":"40","author":"Rosenberg MJ","year":"1995","journal-title":"J Reprod 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