{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T06:10:43Z","timestamp":1761718243435},"reference-count":22,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,5,20]],"date-time":"2013-05-20T00:00:00Z","timestamp":1369008000000},"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":[[2013,6]]},"abstract":"Aim<\/jats:title>To investigate the effects of the cytochrome P450 3A4 (CYP3A4<\/jats:styled-content>) inhibitor ketoconazole on the pharmacokinetics (PK<\/jats:styled-content>) and pharmacodynamics of fluticasone furoate (FF<\/jats:styled-content>) and vilanterol trifenatate (VI<\/jats:styled-content>).<\/jats:p><\/jats:sec>Methods<\/jats:title>Two double\u2010blind, randomized, placebo\u2010controlled, two\u2010way crossover studies in healthy subjects. In study 1, subjects received single doses of ketoconazole (400\u2009mg) or placebo on days 1\u20136, with a single dose of inhaled VI<\/jats:styled-content> (25\u2009\u03bcg) on day 5. Pharmacodynamic and PK<\/jats:styled-content> data were obtained up to 48\u2009h following the VI<\/jats:styled-content> dose. In study 2, subjects received once daily ketoconazole (400\u2009mg) or placebo for 11 days, with FF<\/jats:styled-content>\/VI<\/jats:styled-content> (200\/25\u2009\u03bcg) for the final 7 days. Pharmacodynamic and PK<\/jats:styled-content> data were obtained up to 48\u2009h following the day 11 dose.<\/jats:p><\/jats:sec>Results<\/jats:title>I<\/jats:styled-content>n study 1, there was no effect of co\u2010administration of ketoconazole and VI<\/jats:styled-content> on pharmacodynamic or PK<\/jats:styled-content> parameters. In study 2, co\u2010administration of ketoconazole and FF<\/jats:styled-content>\/VI<\/jats:styled-content> had no effect on 0\u20134\u2009h maximal heart rate or minimal blood potassium {treatment difference [90% confidence interval (CI<\/jats:styled-content>)] \u20130.6 beats\u2009min\u20131<\/jats:sup> (\u22125.8, 4.5) and 0.04\u2009mmol\u2009l\u22121<\/jats:sup> (\u22120.03, 0.11), respectively}, whilst there was a 27% decrease in 24\u2009h weighted mean serum cortisol [treatment ratio (90% CI<\/jats:styled-content>) 0.73 (0.62, 0.86)]. Co\u2010administration of ketoconazole increased [percentage change (90% CI<\/jats:styled-content>)] FF<\/jats:styled-content> area under the curve (0\u201024) and maximal plasma concentration by 36% (16, 59) and 33% (12, 58), respectively, and VI area under the curve <\/jats:styled-content>(0\u2013t<\/jats:italic>\u2032) and maximal plasma concentration by 65% (38, 97) and 22% (8, 38), respectively.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>C<\/jats:styled-content>o\u2010administration of FF<\/jats:styled-content>\/VI<\/jats:styled-content> or VI<\/jats:styled-content> with ketoconazole resulted in a less than twofold increase in systemic exposure to FF<\/jats:styled-content> and VI<\/jats:styled-content>. There was no increase in \u03b2\u2010agonist systemic pharmacodynamic effects, while serum cortisol was decreased by 27%. Co\u2010administration of FF<\/jats:styled-content>\/VI<\/jats:styled-content> with strong CYP3A4<\/jats:styled-content> inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.12019","type":"journal-article","created":{"date-parts":[[2012,11,1]],"date-time":"2012-11-01T12:02:17Z","timestamp":1351771337000},"page":"1478-1487","source":"Crossref","is-referenced-by-count":21,"title":["The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects"],"prefix":"10.1111","volume":"75","author":[{"given":"Rodger","family":"Kempsford","sequence":"first","affiliation":[{"name":"GlaxoSmithKline R&D Stevenage Hertfordshire SG1\u20092NY UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann","family":"Allen","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline R&D Stevenage Hertfordshire SG1\u20092NY UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne","family":"Bal","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline R&D Stockley Park Middlesex UB11 1BT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Rubin","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline R&D Research Triangle Park NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee","family":"Tombs","sequence":"additional","affiliation":[{"name":"Synergy Statistics and Programming Slough Berkshire SL3 6EZ UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,5,20]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"55","volume-title":"Drug\u2010Drug Interactions","author":"Clarke SE","year":"2002"},{"issue":"54","key":"e_1_2_9_3_1","first-page":"1013s","article-title":"Dose\u2010related efficacy of vilanterol trifenatate (VI), a long\u2010acting beta2 agonist (LABA) with inherent 24\u2010hour activity, in patients with persistent asthma","volume":"36","author":"L\u00f6tvall J","year":"2010","journal-title":"Eur Respir J"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.11-2231"},{"key":"e_1_2_9_5_1","first-page":"A4461","article-title":"The pharmacodynamics, pharmacokinetics and tolerability of repeat doses of the novel inhaled long\u2010acting beta2 adrenoceptor agonist (LABA) GW642444 (25, 50 and 100mcg) in healthy subjects","volume":"181","author":"Kempsford RD","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2010.02414.x"},{"key":"e_1_2_9_7_1","first-page":"21","volume-title":"Therapeutic Drugs","author":"Dollery C","year":"1991"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200039001-00001"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(99)70009-3"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-9236(95)90067-5"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp900132e"},{"key":"e_1_2_9_12_1","unstructured":"FDA.1996FDA. 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