{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T06:51:41Z","timestamp":1762325501079,"version":"3.40.5"},"reference-count":23,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T00:00:00Z","timestamp":1672099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Agile Therapeutics, Inc."}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objective<\/jats:title>\n<jats:p>This study employed population pharmacokinetic (popPK) models to predict levonorgestrel (LNG) and ethinyl estradiol (EE) exposure after dosing with the transdermal contraceptive TWIRLA<jats:sup>\u00ae<\/jats:sup> (LNG\/EE TDS) as a 12-week extended regimen in a healthy female population.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>PopPK models were developed using data from a previously published phase 1, open-label, randomized clinical trial, ATI-CL14 (NCT01243580), in 36 healthy individuals. Models used cycle 2 data from 18 individuals who received the LNG\/EE TDS, delivering LNG 120 \u03bcg\/day and EE 30 \u03bcg\/day, followed by a 1-week TDS-free period. Noncompartmental PK analyses were performed on simulated concentration\u2013time profiles of 12 consecutive weeks of LNG\/EE TDS use.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The simulated concentration\u2013time profiles and PK parameters for the simulated extended regimen indicated that predicted LNG and EE exposures at week 12 were similar to week 3 (predicted geometric mean EE area under the concentration-time curve from time 0 to 168 h [AUC<jats:sub>0-168<\/jats:sub>] on week 3 was 0.2% lower than week 12 and LNG AUC<jats:sub>0-168<\/jats:sub> on week 3 was 0.9% lower than week 12), suggesting both were at steady state by week 3. Therefore, no notable accumulation beyond that at week 3 is predicted for LNG and EE following a 12-week extended regimen. The results are supported by the accumulation ratios based on maximum concentration and the area under the curve being similar at weeks 3 and 12 for LNG and EE.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>These results indicate that a 12-week extended LNG\/EE regimen would provide similar systemic hormonal exposure as that seen by week 3 in a standard 28-day regimen, without further hormonal accumulation. The data support the safe use of a non-daily, low-dose hormonal contraceptive in an extended regimen but should be confirmed in a clinical PK study.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0279640","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T18:31:16Z","timestamp":1672165876000},"page":"e0279640","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Extended regimen of a levonorgestrel\/ethinyl estradiol transdermal delivery system: Predicted serum hormone levels using a population pharmacokinetic model"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3607-121X","authenticated-orcid":true,"given":"Frank Z.","family":"Stanczyk","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David F.","family":"Archer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren R. L.","family":"Lohmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Pirone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Previtera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Korner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,12,27]]},"reference":[{"key":"pone.0279640.ref001","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1186\/1471-2458-12-838","article-title":"Adherence to the oral contraceptive pill: a cross-sectional survey of modifiable behavioural determinants","volume":"12","author":"GJ Molloy","year":"2012","journal-title":"BMC Public Health"},{"issue":"2","key":"pone.0279640.ref002","doi-asserted-by":"crossref","DOI":"10.2307\/2991665","article-title":"Compliance, counseling and satisfaction with oral contraceptives: a prospective evaluation","volume":"30","author":"MJ Rosenberg","year":"1998","journal-title":"Fam Plann Perspect"},{"key":"pone.0279640.ref003","doi-asserted-by":"crossref","first-page":"74S","DOI":"10.1097\/01.AOG.0000463154.89957.a3","article-title":"Measuring Adherence to Birth Control Pills Among College Women [229]","volume":"125","author":"CA Wiltjer","year":"2015","journal-title":"Obstetrics & Gynecology"},{"key":"pone.0279640.ref004","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1472-6874-13-38","article-title":"Evaluation of factors associated with noncompliance in users of combined hormonal contraceptive methods: a cross-sectional study: results from the MIA study","volume":"13","author":"T Mart\u00ednez-Astorquiza-Ortiz de Zarate","year":"2013","journal-title":"BMC Womens Health"},{"issue":"2","key":"pone.0279640.ref005","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/S0002-9378(99)70718-0","article-title":"Causes and consequences of oral contraceptive noncompliance","volume":"180","author":"M Rosenberg","year":"1999","journal-title":"Am J Obstet Gynecol"},{"issue":"2","key":"pone.0279640.ref006","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1016\/S0015-0282(01)03263-0","article-title":"Assessment of compliance with a weekly contraceptive patch (Ortho Evra\/Evra) among North American women","volume":"77","author":"DF Archer","year":"2002","journal-title":"Fertil Steril"},{"issue":"10","key":"pone.0279640.ref007","doi-asserted-by":"crossref","first-page":"849","DOI":"10.3109\/09513590.2010.538095","article-title":"High levels of women\u2019s satisfaction and compliance with transdermal contraception: results from a European multinational, 6-month study","volume":"27","author":"AJ Jakimiuk","year":"2011","journal-title":"Gynecol Endocrinol"},{"issue":"4","key":"pone.0279640.ref008","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/S1701-2163(16)30462-5","article-title":"Preference for and satisfaction of Canadian women with the transdermal contraceptive patch versus previous contraceptive method: an open-label, multicentre study","volume":"27","author":"F Weisberg","year":"2005","journal-title":"J Obstet Gynaecol Can"},{"issue":"5","key":"pone.0279640.ref009","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.contraception.2004.06.008","article-title":"Women\u2019s and providers\u2019 attitudes toward menstrual suppression with extended use of oral contraceptives","volume":"70","author":"LC Andrist","year":"2004","journal-title":"Contraception"},{"issue":"6","key":"pone.0279640.ref010","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S0010-7824(99)00043-8","article-title":"Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement therapy use","volume":"59","author":"I den Tonkelaar","year":"1999","journal-title":"Contraception"},{"key":"pone.0279640.ref011","unstructured":"Lybrel (levonorgestrel and ethinyl estradiol tablets) [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc."},{"key":"pone.0279640.ref012","unstructured":"Seasonique (levonorgestrel\/ethinyl estradiol tablets and ethinyl estradiol tablets) [package insert]. Pomona, NY: Duramed Pharmaceuticals, Inc; July 2010."},{"key":"pone.0279640.ref013","unstructured":"LoSeasonique (levonorgestrel\/ethinyl estradiol tablets and ethinyl estradiol tablets) [package insert]. Pomona, NY: Duramed Pharmaceuticals Inc; 2008."},{"key":"pone.0279640.ref014","unstructured":"Quartette (levonorgestrel\/ethinyl estradiol and ethinyl estradiol tablets) [package insert]. Sellersville, PA: Teva Pharmaceuticals USA, Inc.; March 2013."},{"key":"pone.0279640.ref015","unstructured":"Twirla (levonorgestrel and ethinyl estradiol transdermal system) [package insert]. Princeton, NJ: Agile Therapeutics, Inc.; 2020."},{"issue":"6","key":"pone.0279640.ref016","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.contraception.2011.10.006","article-title":"Ethinyl estradiol and levonorgestrel pharmacokinetics with a low-dose transdermal contraceptive delivery system, AG200-15: a randomized controlled trial","volume":"85","author":"DF Archer","year":"2012","journal-title":"Contraception"},{"issue":"3","key":"pone.0279640.ref017","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.contraception.2017.09.010","article-title":"Women\u2019s perceptions and treatment patterns related to contraception: results of a survey of US women","volume":"97","author":"AL Nelson","year":"2018","journal-title":"Contraception"},{"issue":"3","key":"pone.0279640.ref018","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.contraception.2020.11.011","article-title":"Efficacy, safety, and tolerability of a levonorgestrel\/ethinyl estradiol transdermal delivery system: Phase 3 clinical trial results","volume":"103","author":"AL Nelson","year":"2021","journal-title":"Contraception"},{"issue":"3","key":"pone.0279640.ref019","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.contraception.2014.11.011","article-title":"Self-reported and verified compliance in a phase 3 clinical trial of a novel low-dose contraceptive patch and pill","volume":"91","author":"AM Kaunitz","year":"2015","journal-title":"Contraception"},{"key":"pone.0279640.ref020","unstructured":"TWIRLA (levonorgestrel and ethinyl estradiol) transdermal system [prescribing information]. Princeton, NJ: Agile Therapeutics, Inc; February 2020."},{"issue":"1","key":"pone.0279640.ref021","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.contraception.2016.08.003","article-title":"Clarification of contraceptive drug pharmacokinetics in obesity","volume":"95","author":"WJ Jusko","year":"2017","journal-title":"Contraception"},{"issue":"1","key":"pone.0279640.ref022","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.contraception.2010.06.015","article-title":"Steady-state pharmacokinetics of an extended-regimen oral contraceptive with continuous estrogen","volume":"83","author":"CE DiLiberti","year":"2011","journal-title":"Contraception"},{"issue":"11","key":"pone.0279640.ref023","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1177\/1933719114526472","article-title":"A comparison of the pharmacokinetic profile of an ascending-dose, extended-regimen combined oral contraceptive to those of other extended regimens","volume":"21","author":"M Darwish","year":"2014","journal-title":"Reprod Sci"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0279640","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T18:31:35Z","timestamp":1672165895000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0279640"}},"subtitle":[],"editor":[{"given":"George","family":"Vousden","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,12,27]]},"references-count":23,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0279640","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2022,12,27]]}}}