title: Effect of itraconazole on the pharmacokinetics of imidafenacin in healthy subjects.
abstract: The effect of itraconazole, a potent inhibitor of the CYP3A isoenzyme family, on the pharmacokinetics of imidafenacin, a novel synthetic muscarinic receptor antagonist, was investigated. Twelve healthy subjects participated in this open-label, self-controlled study. In period I, subjects received a single oral dose of 0.1 mg imidafenacin. In period II, they received multiple oral doses of 200 mg itraconazole for 9 days and a single oral dose of 0.1 mg imidafenacin on day 8. Plasma concentrations of imidafenacin and M-2, the major metabolite of imidafenacin metabolized by CYP3A4, were determined. Analytes were measured by liquid chromatography tandem mass spectrometry. Following coadministration with itraconazole, the maximum plasma concentration (C(max)) of imidafenacin increased 1.32-fold (90% confidence intervals [CIs]: 1.12-1.56), and the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) increased 1.78-fold (90% CI: 1.47-2.16). In conclusion, itraconazole increases the plasma concentrations of imidafenacin by inhibiting CYP3A4. Therefore, itraconazole or potent CYP3A4 inhibitors should be carefully added to imidafenacin drug regimens.
authors.affiliation: Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co. Ltd., 17-2 Wadai Tsukuba, Ibaraki, Japan. to.ohno@ono.co.jp
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ohno
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakayama
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakade
authors.forename: Junsaku
authors.initials: J
authors.lastname: Kitagawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyabe
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Miyata
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ohnishi
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017964:Itraconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D010352:Patient Dropouts; D013607:Tablets; D053719:Tandem Mass Spectrometry
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D007093:Imidazoles; D018727:Muscarinic Antagonists; D013607:Tablets; D017964:Itraconazole; D051544:Cytochrome P-450 CYP3A; C120953:imidafenacin