Lack of dose-dependent effects of itraconazole on the pharmacokinetic interaction with fexofenadine

Tsukasa Uno, Mikiko Shimizu, Kazunobu Sugawara, Tomonori Tateishi

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 (AUC0-∞) 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 AUC0-48 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), Cmax (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.

Original languageEnglish
Pages (from-to)1875-1879
Number of pages5
JournalDrug Metabolism and Disposition
Volume34
Issue number11
DOIs
Publication statusPublished - 2006
Externally publishedYes

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fexofenadine
Pharmacokinetics
Itraconazole
Kidney
Plasmas
Phase control

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Lack of dose-dependent effects of itraconazole on the pharmacokinetic interaction with fexofenadine. / Uno, Tsukasa; Shimizu, Mikiko; Sugawara, Kazunobu; Tateishi, Tomonori.

In: Drug Metabolism and Disposition, Vol. 34, No. 11, 2006, p. 1875-1879.

Research output: Contribution to journalArticle

Uno, Tsukasa ; Shimizu, Mikiko ; Sugawara, Kazunobu ; Tateishi, Tomonori. / Lack of dose-dependent effects of itraconazole on the pharmacokinetic interaction with fexofenadine. In: Drug Metabolism and Disposition. 2006 ; Vol. 34, No. 11. pp. 1875-1879.
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N2 - 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 (AUC0-∞) 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 AUC0-48 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), Cmax (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.

AB - 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 (AUC0-∞) 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 AUC0-48 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), Cmax (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.

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