{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T21:58:17Z","timestamp":1784757497935,"version":"3.55.0"},"reference-count":35,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2017,5,18]],"date-time":"2017-05-18T00:00:00Z","timestamp":1495065600000},"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":[[2017,9]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The pharmacokinetics of voriconazole show a nonlinear dose\u2013exposure relationship caused by inhibition of its own CYP3A\u2010dependent metabolism. Because the magnitude of autoinhibition also depends on voriconazole concentrations, infusion rate might modulate voriconazole exposure. The impact of four different infusion rates on voriconazole pharmacokinetics was investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twelve healthy participants received 100\u00a0mg voriconazole intravenous over 4\u00a0h, 400\u00a0mg over 6\u00a0h, 4\u00a0h, and 2\u00a0h in a crossover design. Oral midazolam (3\u00a0\u03bcg) was given at the end of infusion. Blood and urine samples were collected up to 48\u00a0h. Voriconazole and its N\u2010oxide metabolite were quantified using high\u2010performance liquid chromatography coupled to tandem mass spectrometry. Midazolam estimated metabolic clearance (eCLmet) was calculated using a limited sampling strategy. Voriconazole\u2010N\u2010oxide inhibition of cytochrome P450 (CYP) isoforms 2C19 and 3A4 were assessed with the P450\u2010Glo luminescence assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Area under the concentration\u2013time curve for 400\u00a0mg intravenous voriconazole was 16% (90% confidence interval: 12\u201320%) lower when administered over 6\u00a0h compared to 2\u00a0h infusion. Dose\u2010corrected area under the concentration\u2013time curve for 100\u00a0mg over 4\u00a0h was 34% lower compared to 400\u00a0mg over 4\u00a0h. Midazolam eCLmet was 516\u00a0ml\u00a0min<jats:sup>\u20131<\/jats:sup> (420\u2013640) following 100\u00a0mg\u00a04\u00a0h<jats:sup>\u20131<\/jats:sup> voriconazole, 152\u00a0ml\u00a0min<jats:sup>\u20131<\/jats:sup> (139\u2013166) for 400\u00a0mg\u00a06\u00a0h<jats:sup>\u20131<\/jats:sup>, 192\u00a0ml\u00a0min<jats:sup>\u20131<\/jats:sup> (167\u2013220) for 400\u00a0mg\u00a04\u00a0h<jats:sup>\u22121<\/jats:sup>, and 202\u00a0ml\u00a0min<jats:sup>\u20131<\/jats:sup> (189\u2013217) for 400\u00a0mg\u00a02\u00a0h<jats:sup>\u20131<\/jats:sup>. Concentration giving 50% CYP inhibition of voriconazole N\u2010oxide was 146\u00a0\u00b1\u00a023\u00a0\u03bcmol\u00a0l<jats:sup>\u20131<\/jats:sup> for CYP3A4, and 40.2\u00a0\u00b1\u00a04.2\u00a0\u03bcmol\u00a0l<jats:sup>\u20131<\/jats:sup> for CYP2C19.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Voriconazole pharmacokinetics is modulated by infusion rate, an autoinhibitory contribution voriconazole metabolism by CYP3A and 2C19 and to a lesser extent its main N\u2010oxide metabolite for CYP2C19. To avoid reduced exposure, the infusion rate should be 2\u00a0h.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13297","type":"journal-article","created":{"date-parts":[[2017,3,29]],"date-time":"2017-03-29T15:26:49Z","timestamp":1490801209000},"page":"1954-1965","source":"Crossref","is-referenced-by-count":24,"title":["Autoinhibitory properties of the parent but not of the N\u2010oxide metabolite contribute to infusion rate\u2010dependent voriconazole pharmacokinetics"],"prefix":"10.1111","volume":"83","author":[{"given":"Nicolas","family":"Hohmann","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology University Hospital Heidelberg  Im Neuenheimer Feld 410 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Kreuter","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology University Hospital Heidelberg  Im Neuenheimer Feld 410 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Blank","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology University Hospital Heidelberg  Im Neuenheimer Feld 410 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology University Hospital Heidelberg  Im Neuenheimer Feld 410 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Burhenne","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology University Hospital Heidelberg  Im Neuenheimer Feld 410 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter E.","family":"Haefeli","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology University Hospital Heidelberg  Im Neuenheimer Feld 410 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1783-133X","authenticated-orcid":false,"given":"Gerd","family":"Mikus","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology University Hospital Heidelberg  Im Neuenheimer Feld 410 69120 Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,5,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1037"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13354"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis437"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e31817b1a95"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.31.6.731"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.107.019646"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.04.004"},{"key":"e_1_2_11_9_1","unstructured":"Pfizer PFE GmbH (Germany).Vfend\u00ae summary of product characteristics. 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