{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T09:32:56Z","timestamp":1791019976433,"version":"4.1.0"},"reference-count":16,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2012,4,5]],"date-time":"2012-04-05T00:00:00Z","timestamp":1333584000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2012,5]]},"abstract":"<jats:sec><jats:label\/><jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Lersivirine (UK\u2010453,061) is predominantly cleared by glucuronidation (UGT2B7) and oxidation via cytochrome P450 (CYP) 3A4.<\/jats:p><jats:p>\u2022\u2003Lersivirine metabolism, and thus pharmacokinetics, may be affected by concomitant administration of drugs affecting CYP3A4 and UGT2B7.<\/jats:p><jats:p>\u2022\u2003Ketoconazole is a potent inhibitor of CYP3A4 and an inhibitor of UGT2B7. Valproic acid is a potent inhibitor of UGT2B7.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Combined inhibition of CYP3A4 and UGT2B7 with ketoconazole increases the exposure of lersivirine, and may warrant lersivirine dose adjustment to compensate for this interaction.<\/jats:p><jats:p>\u2022\u2003Inhibition of UGT2B7 with valproic acid does not have a substantial effect on lersivirine pharmacokinetics.<\/jats:p><\/jats:sec><jats:sec><jats:title>AIMS<\/jats:title><jats:p>To investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK\u2010453,061), a next generation non\u2010nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co\u2010administration of lersivirine with these inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Two open\u2010label, randomized, placebo\u2010controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400\u2003mg once daily) on the pharmacokinetics of lersivirine (250\u2003mg once daily). Subjects received ketoconazole 400\u2003mg once daily or placebo on days 1\u20132 and received lersivirine 250\u2003mg once daily and ketoconazole 400\u2003mg once daily or placebo on days 3\u20139. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000\u2003mg once daily) on the PK of lersivirine (500\u2003mg once daily). On days 1\u20137, subjects received lersivirine 500\u2003mg once daily plus either VPA 1000\u2003mg or placebo.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Compared with lersivirine alone, co\u2010administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24\u2003h)) and maximum plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24\u2003h) by 25% (90% CI 16%, 35%), with little effect on <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> (2.5%, 90% CI \u22129%, 16%). There were no serious adverse events and no treatment\u2010related discontinuations from either study.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Inhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7\u2010mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co\u2010administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2125.2011.04136.x","type":"journal-article","created":{"date-parts":[[2011,11,1]],"date-time":"2011-11-01T06:21:44Z","timestamp":1320128504000},"page":"768-775","source":"Crossref","is-referenced-by-count":15,"title":["Effects of ketoconazole and valproic acid on the pharmacokinetics of the next generation NNRTI, lersivirine (UK\u2010453,061), in healthy adult subjects"],"prefix":"10.1111","volume":"73","author":[{"given":"Grant","family":"Langdon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Layton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chew\u2010Lan","family":"Chong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georges","family":"Weissgerber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoli","family":"Vourvahis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,4,5]]},"reference":[{"key":"e_1_2_7_2_2","unstructured":"Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the use of antiretroviral agents in HIV\u20101\u2010infected adults and adolescents. 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Available athttp:\/\/www.intelence\u2010info.com\/sites\/default\/files\/pdf\/INTELENCE_Booklet_Package_Insert_hcp.pdf. Updated 2011 (last accessed 28 June 2011)."},{"key":"e_1_2_7_15_2","unstructured":"Van HeeswijkR HoetelmansR KestensD StevensM PeetersM WilliamsP WoodfallB BovenK.The pharmacokinetic interaction between ketoconazole and TMC278 an investigational non\u2010nucleoside reverse transcriptase inhibitior (NNRTI) in healthy HIV\u2010negative subjects. Paper presented at the XVI International AIDS Conference Toronto Canada 13\u201318 August 2006."},{"key":"e_1_2_7_16_2","unstructured":"McFadyenL WeatherleyB VourvahisM.Preliminary lersivirine population pharmacokinetics in treatment\u2010naive HIV\u20101\u2010infected subjects receiving lersivirine (UK\u2010453 061) and tenofovir\/emtricitabine in a Phase 2b study. 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