title: Lack of dose-dependent effects of itraconazole on the pharmacokinetic interaction with fexofenadine.
abstract: The aim of this study was to determine the inhibitory effect of itraconazole at different coadministered doses on fexofenadine pharmacokinetics. In a randomized four-phase crossover study, 11 healthy volunteers were administered a 60-mg fexofenadine hydrochloride tablet alone on one occasion (control phase) and with three different doses of 50, 100, and 200 mg of itraconazole simultaneously on the other three occasions (itraconazole phase). Although the elimination half-life and the renal clearance of fexofenadine remained relatively constant, a single administration of itraconazole with fexofenadine significantly increased mean area under the plasma concentration-time curve (AUC(0-infinity)) of fexofenadine (1701/3554, 4308, and 4107 ng h/ml for control; 50 mg, 100 mg, and 200 mg of itraconazole, respectively). Although mean itraconazole AUC(0-48) from 50 mg to 200 mg increased dose dependently from 214 to 772 ng h/ml (p = 0.003), no significant difference was noted in the three parameters, AUC (p = 0.423), C(max) (p = 0.636), and renal clearance (p = 0.495), of fexofenadine among the three doses of itraconazole. Itraconazole exposure at a lower dose (50 mg) compared with the clinical dose (200 mg once or twice daily) had the maximal effect on fexofenadine pharmacokinetics, even though itraconazole plasma concentrations gradually increased after higher doses. These findings suggest that the interaction may occur at the gut wall before reaching the portal vein circulation, and the inhibitory effect must be saturated by substantial local concentrations of itraconazole in the gut lumen after 50-mg dosing.
authors.affiliation: Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki, Japan. uno-hki@umin.ac.jp
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Uno
authors.forename: Mikiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Sugawara
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tateishi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D039563:Histamine H1 Antagonists, Non-Sedating / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D039563:Histamine H1 Antagonists, Non-Sedating; D017964:Itraconazole; D016593:Terfenadine; C093230:fexofenadine