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Capturing the time course of inhibition is therefore difficult using standard DDI studies assessing changes in area under the curve; thus, a novel design was developed. In a 4\u2010period changeover pilot study, 6 healthy men received intraduodenal or intravenous infusions of the CYP3A substrate midazolam (MDZ) at a rate of 0.26 mg\/h for 24 hours. This was combined with intraduodenal or intravenous infusion of the CYP3A inhibitor voriconazole (VRZ), administered at rates of 7.5 mg\/h from 8 to 16 hours and of 15 mg\/h from 16 to 24 hours, after starting midazolam administration. Plasma and urine concentrations of VRZ, MDZ, and its major metabolites were quantified by liquid chromatography\u2010tandem mass spectrometry and analyzed by semiphysiological population pharmacokinetic nonlinear mixed\u2010effects modeling. A model including mechanism\u2010based inactivation of the metabolizing enzymes (maximum inactivation rate constant k<jats:sub>inact<\/jats:sub>, 2.83 h<jats:sup>\u22121<\/jats:sup>; dissociation rate constant <jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/jcph1619-math-0001.png\" xlink:title=\"urn:x-wiley:00912700:media:jcph1619:jcph1619-math-0001\"\/>, 9.33 \u03bcM) described the pharmacokinetics of VRZ well. By introducing competitive inhibition by VRZ on primary and secondary MDZ metabolism, concentration\u2010time profiles, MDZ and its metabolites were captured appropriately. The model provides estimates of local concentrations of substrate and inhibitor at the major CYP3A expression sites and thus of the respective dynamic extent of inhibition. A combination of intravenous and intraduodenal infusions of inhibitors and substrates has the potential to provide a more accurate assessment of DDIs occurring in both gut wall and liver.<\/jats:p>","DOI":"10.1002\/jcph.1619","type":"journal-article","created":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T21:07:58Z","timestamp":1589922478000},"page":"1237-1253","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Novel Study Design Using Continuous Intravenous and Intraduodenal Infusions of Midazolam and Voriconazole for Mechanistic Quantitative Assessment of Hepatic and Intestinal CYP3A Inhibition"],"prefix":"10.1002","volume":"60","author":[{"given":"Xia","family":"Li","sequence":"first","affiliation":[{"name":"University of Cologne, Faculty of Medicine and University Hospital Cologne Center for Pharmacology Department I of Pharmacology  Cologne 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