{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T11:48:38Z","timestamp":1782906518294,"version":"3.54.5"},"reference-count":33,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,2,14]],"date-time":"2017-02-14T00:00:00Z","timestamp":1487030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biopharm &amp; Drug Disp"],"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The impact of different single oral doses of ketoconazole (KTZ) (100, 200 and 400\u00a0mg) and of staggering its dosage (400\u00a0mg at \u221212, \u22122, 0, 2 and 4\u00a0h), with respect to the administration of a single 5\u00a0mg oral dose of midazolam (MDZ) on the extent of inhibition of the metabolism of the latter, was evaluated in healthy subjects in two separate studies. Escalation of the ketoconazole dosage resulted in 2.3 (1.9), 2.7 (1.7) and 4.2 (2.5) \u2010fold increases in the mean<jats:italic>AUC<\/jats:italic><jats:sub>(0,12h)<\/jats:sub>(and<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) values of midazolam. Dose\u2010staggering was associated with 3.9 (2.5), 4.9 (2.9), 5.4 (2.8), 2.0 (1.3) and 1.2 (0.9) \u2010fold increases in the mean<jats:italic>AUC<\/jats:italic><jats:sub>(0,12h)<\/jats:sub>(and<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) of midazolam. These findings could be predicted by physiologically based pharmacokinetic (PBPK) modelling using the ADAM (advanced dissolution absorption and metabolism) model within the Simcyp Simulator (Version 12 Release 2) to characterize the absorption kinetics of ketoconazole with respect to disintegration time, supersaturation ratio and precipitation rate. This study also emphasizes a need to account for inter\u2010individual variability in the gut wall and systemic exposure of inhibitors with physicochemical properties similar to ketoconazole, in particular in their rate of oral absorption and when using different pharmaceutical formulations, in designing and evaluating the extent of drug\u2013drug interactions. Copyright \u00a9 2016 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/bdd.2058","type":"journal-article","created":{"date-parts":[[2016,12,22]],"date-time":"2016-12-22T02:47:15Z","timestamp":1482374835000},"page":"260-270","source":"Crossref","is-referenced-by-count":16,"title":["The absorption kinetics of ketoconazole plays a major role in explaining the reported variability in the level of interaction with midazolam: Interplay between formulation and inhibition of gut wall and liver metabolism"],"prefix":"10.1002","volume":"38","author":[{"given":"Bo","family":"Liu","sequence":"first","affiliation":[{"name":"Simcyp Ltd, Blades Enterprise Centre John Street Sheffield S2 4SU UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Kim","family":"Crewe","sequence":"additional","affiliation":[{"name":"Simcyp Ltd, Blades Enterprise Centre John Street Sheffield S2 4SU UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmut","family":"Ozdemir","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine Eski\u015fehir Osmangazi University Eski\u015fehir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Rowland Yeo","sequence":"additional","affiliation":[{"name":"Simcyp Ltd, Blades Enterprise Centre John Street Sheffield S2 4SU UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Tucker","sequence":"additional","affiliation":[{"name":"Department of Human Metabolism (Emeritus), Medicine and Biomedical Sciences University of Sheffield Sheffield S10 2JF UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3917-844X","authenticated-orcid":false,"given":"Amin","family":"Rostami\u2010Hodjegan","sequence":"additional","affiliation":[{"name":"Simcyp Ltd, Blades Enterprise Centre John Street Sheffield S2 4SU UK"},{"name":"Manchester Pharmacy School Stopford Building, Oxford Road Manchester M13 9PT UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,2,14]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-014-0235-4"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1990.tb03705.x"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-004-1185-3"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-198308010-00002"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/8.4.299"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.25.1.1"},{"key":"e_1_2_5_8_1","first-page":"5365","article-title":"Evaluation of bioequivalence of two formulations containing 200\u00a0mg of ketoconazole","volume":"19","author":"Solomon W","year":"2007","journal-title":"Asian J Chem"},{"key":"e_1_2_5_9_1","first-page":"482","article-title":"Comparative bioavailability study of two ketoconazole tablet preparation","volume":"54","author":"Yuen K","year":"1999","journal-title":"Med J Malasia"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-198223010-00001"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600750504"},{"key":"e_1_2_5_12_1","first-page":"6","article-title":"Bioequivalency study of two formulations of ketoconazole tablet in healthy volunteers","volume":"1","author":"Sadeghnia H","year":"2005","journal-title":"Iran J Pharm Res"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-009-9099-y"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498250600683197"},{"key":"e_1_2_5_15_1","unstructured":"Rowland YeoK JameiM TuckerGT Rostami\u2010HodjeganA.Prediction of the inhibitory effects of ketaconazole and fluconazole on midazolam and zolpidem clearance fromin vitrodata using physiologically\u2010based pharmacokinetic modelling. Presented at9th International Conference on Drug\u2013Drug Interactions Seattle WA 2006."},{"key":"e_1_2_5_16_1","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/S0090-9556(24)15274-9","article-title":"Inhibition of cytochrome P\u2010450 3A (CYP3A) in human intestinal and liver microsomes: comparison of K i values and impact of CYP3A5 expression","volume":"27","author":"Gibbs MA","year":"1999","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0928-0987(03)00200-8"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.059311"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2007.05.008"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.10039"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/js980236p"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1016212804288"},{"key":"e_1_2_5_23_1","first-page":"1334","article-title":"Effect of pH on disintegration and dissolution of ketoconazole tablets","volume":"40","author":"Carlson JA","year":"1983","journal-title":"Am J Hosp Pharm"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2016.01.027"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1981.217"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-198461010-00006"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.1983.tb04302.x"},{"key":"e_1_2_5_28_1","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1016\/S0022-3565(24)37149-6","article-title":"Characterization of interintestinal and intraintestinal variations in human CYP3A\u2010dependent metabolism","volume":"283","author":"Paine MF","year":"1997","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1983.tb02270.x"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1982.133"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.106013"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.30.2.206"},{"key":"e_1_2_5_33_1","first-page":"271","article-title":"Serum binding of ketoconazole in health and disease","volume":"10","author":"Martinez\u2010Jorda R","year":"1990","journal-title":"Int J Clin Pharmacol Res"},{"key":"e_1_2_5_34_1","first-page":"1","article-title":"Improvement of solubility and dissolution properties of ketoconazole by solid dispersions and inclusion complexes","volume":"5","author":"Balata G","year":"2010","journal-title":"Asian J Pharm Sci"}],"container-title":["Biopharmaceutics &amp; Drug Disposition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdd.2058","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdd.2058","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T20:16:55Z","timestamp":1749845815000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdd.2058"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,14]]},"references-count":33,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2017,4]]}},"alternative-id":["10.1002\/bdd.2058"],"URL":"https:\/\/doi.org\/10.1002\/bdd.2058","archive":["Portico"],"relation":{},"ISSN":["0142-2782","1099-081X"],"issn-type":[{"value":"0142-2782","type":"print"},{"value":"1099-081X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,14]]}}}