{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T01:42:51Z","timestamp":1774316571019,"version":"3.50.1"},"reference-count":29,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T00:00:00Z","timestamp":1554076800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003323","name":"Agence Nationale de Recherches sur le Sida et les H\u00e9patites Virales","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003323","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009947","name":"Merck Sharp and Dohme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009947","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2019,4]]},"abstract":"Study Objective<\/jats:title>The ANRS<\/jats:styled-content>163\u2010ETRAL<\/jats:styled-content> study showed that etravirine 200\u00a0mg\/raltegravir 400\u00a0mg twice\u2010daily dual therapy was highly effective in the treatment of human immunodeficiency virus (HIV<\/jats:styled-content>)\u2010infected patients older than 45\u00a0years, with virologic and therapeutic success rates at week 48 of 99.4% and 94.5%, respectively. The objective of this study was to determine whether a clinically significant pharmacokinetic interaction between etravirine and raltegravir exists by assessing steady\u2010state total and unbound etravirine, raltegravir, and inactive raltegravir\u2010glucuronide concentrations 12\u00a0hours after last intake (C12h<\/jats:sub>) in blood plasma (BP<\/jats:styled-content>) and seminal plasma (SP<\/jats:styled-content>).<\/jats:p><\/jats:sec>Design<\/jats:title>Pharmacokinetic analysis of data from the ANRS<\/jats:styled-content>163\u2010ETRAL<\/jats:styled-content> study.<\/jats:p><\/jats:sec>Patients<\/jats:title>One hundred forty\u2010six HIV<\/jats:styled-content>\u20101\u2013infected patients (of the 165 patients included in the ANRS<\/jats:styled-content>\u2010163 ETRAL<\/jats:styled-content> study) who were receiving etravirine 200\u00a0mg and raltegravir 400\u00a0mg twice daily.<\/jats:p><\/jats:sec>Measurements and Main Results<\/jats:title>Blood was collected from all 146 patients at weeks 2\u20134, 12, 24, and 48, and semen was collected from 21 patients at week 48. The extent of BP<\/jats:styled-content> and SP<\/jats:styled-content> protein binding was determined by using ultrafiltration assay. Total and unbound etravirine, raltegravir, and raltegravir\u2010glucuronide C12h<\/jats:sub> were determined by ultra high performance liquid chromatography coupled with tandem mass spectrometry and interpreted by using the in\u00a0vitro<\/jats:italic> calculated protein\u2010bound 95% inhibitory concentration (PBIC<\/jats:styled-content>95<\/jats:sub>) for wild\u2010type (WT<\/jats:styled-content>) HIV<\/jats:styled-content>: etravirine (116\u00a0ng\/ml<\/jats:styled-content>) and raltegravir (15\u00a0ng\/ml<\/jats:styled-content>). Median (interquartile range [IQR<\/jats:styled-content>]) total BP<\/jats:styled-content> etravirine C12h<\/jats:sub> (536\u00a0ng\/ml<\/jats:styled-content> [376\u2013719]) and raltegravir (278\u00a0ng\/ml<\/jats:styled-content> [97\u2013690]) were adequate in 99% and 96% of patients, respectively. Median (IQR<\/jats:styled-content>) SP:BP<\/jats:styled-content> C12h<\/jats:sub> ratio and BP<\/jats:styled-content> unbound fraction were etravirine 0.3 (0.2\u20130.5) and <\u00a01%, respectively, raltegravir 1.8 (1.3\u20133.3) and 12%, respectively, and raltegravir\u2010glucuronide 12.0 (6.5\u201317.7) and >\u00a099%, respectively. The BP<\/jats:styled-content> raltegravir metabolic ratio (raltegravir glucuronide:raltegravir ratio) was 1.7, suggesting only weak induction of raltegravir glucuronidation by etravirine. Only three patients had etravirine and raltegravir C12h<\/jats:sub> <\u00a0PBIC<\/jats:styled-content>95<\/jats:sub> simultaneously.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>No clinically significant pharmacokinetic interaction between etravirine and raltegravir was detected. Total etravirine and raltegravir BP<\/jats:styled-content> concentrations were adequate in most patients, favoring virologic efficacy and confirming good treatment adherence (>\u00a095%), despite twice\u2010daily administration. The long half\u2010life of etravirine and higher unbound fraction SP<\/jats:styled-content> of raltegravir (57%) ensured adequate concentrations of dual therapy in genital compartments. Our results indicate that etravirine and raltegravir have good, complementary pharmacokinetic profiles, suggesting that they could be used in a dual\u2010treatment strategy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/phar.2242","type":"journal-article","created":{"date-parts":[[2019,2,28]],"date-time":"2019-02-28T01:25:56Z","timestamp":1551317156000},"page":"514-520","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Lack of a Clinically Significant Pharmacokinetic Interaction between Etravirine and Raltegravir Using an Original Approach Based on Drug Metabolism, Protein Binding, and Penetration in Seminal Fluid: A Pharmacokinetic Substudy of the ANRS<\/scp>\u2010163 ETRAL<\/scp> Study"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4670-8288","authenticated-orcid":false,"given":"Minh Patrick","family":"L\u00ea","sequence":"first","affiliation":[{"name":"IAME UMR 1137 Sorbonne Paris 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