{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T18:22:37Z","timestamp":1772994157371,"version":"3.50.1"},"reference-count":20,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"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":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    According to the FDA Guidance for Industry on Clinical Drug Interaction (DDI) Studies with Combined Oral Contraceptives (COCs), sponsors are expected to conduct dedicated clinical DDI studies if in vitro findings suggest weak or moderate CYP3A induction, while concomitant use of COCs with strong inducers should be avoided. The guidance further suggests that a negative DDI result for drospirenone (DRSP) may be extrapolated to other progestins that are less sensitive to CYP3A modulation, such as levonorgestrel (LNG). This approach assumes that DDI\u2010mediated changes in exposure directly translate into clinical efficacy across progestins. To evaluate the validity of this assumption, we established a quantitative link between dose, exposure, and response (Pearl Index [PI] and ovulation rate [OR]) via an integrated model\u2010based meta\u2010analysis, physiologically based pharmacokinetic, and pharmacokinetic\/pharmacodynamic (PK\/PD) modeling and simulation approach using data from 51 clinical studies in 36,040 women receiving LNG or DRSP. COCs containing LNG and DRSP were selected because they represent clinically relevant progestins at the lower and the upper end of the fraction metabolized via CYP3A4. The results of our analysis show a moderate correlation (Pearson's r = 0.52, 95% CI 0.46\u20100.58,\n                    <jats:italic>P<\/jats:italic>\n                    \u00a0&lt;\u00a00.001) between PI and OR, which enables the use of OR as an ethically measurable endpoint, even at subtherapeutic doses\/exposures, to predict efficacy outcomes. They further show that DDI\u2010induced changes in exposure do not directly translate into clinical response. Therefore, DDIs with COCs should be interpreted in a PK\/PD rather than a PK\u2010only context. The quantitative framework developed in this study can serve as the scientific basis to do so.\n                  <\/jats:p>","DOI":"10.1002\/jcph.70063","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T08:10:09Z","timestamp":1753171809000},"page":"1855-1863","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Establishing a Quantitative Framework for Combined Oral Contraceptives: Evaluating the Impact of Drug\u2013Drug Interactions on Exposure and Clinical (Surrogate) Efficacy Endpoints"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3309-7883","authenticated-orcid":false,"given":"Dain","family":"Chun","sequence":"first","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2233-727X","authenticated-orcid":false,"given":"Huili","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando FL 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":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando FL 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":"Pop\u2010Pharm Pharmacometrics Service Albany CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8030-0051","authenticated-orcid":false,"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 FL 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":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando FL USA"},{"name":"Model Informed Development CTI Laboratories Covington KY 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":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"U.S. Food and Drug Administration (FDA).Clinical drug interaction studies with combined oral contraceptives guidance for industry [Internet].FDA.2023.https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/clinical\u2010drug\u2010interaction\u2010studies\u2010combined\u2010oral\u2010contraceptives\u2010guidance\u2010industry"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.122.000854"},{"key":"e_1_2_10_4_1","unstructured":"U.S. Food and Drug Administration (FDA).Establishing effectiveness and safety for hormonal drug products intended to prevent pregnancy guidance for industry.2019.https:\/\/www.fda.gov\/media\/128792\/download"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12572"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2690"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(93)90025-3"},{"key":"e_1_2_10_8_1","unstructured":"HoleshJE BassAN LordM.Physiology ovulation.StatPearls 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