Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole.
OBJECTIVE
Our objective was to examine the effects of itraconazole on the pharmacokinetics and cortisol-suppressant activity of budesonide administered by inhalation.


METHODS
In a randomized, double-blind, 2-phase crossover study, 10 healthy subjects took 200 mg itraconazole or placebo orally once a day for 5 days. On day 5, 1 hour after the last dose of itraconazole or placebo, 1000 microg budesonide was administered by inhalation. Plasma budesonide and cortisol concentrations were measured up to 23 hours.


RESULTS
Itraconazole increased the mean total area under the plasma concentration-time curve of inhaled budesonide 4.2-fold (range, 1.7-fold to 9.8-fold; P <.01) and the peak plasma concentration 1.6-fold (P <.01) compared with placebo. The mean terminal half-life of budesonide was prolonged from 1.6 to 6.2 hours (ie, 3.7-fold; range, 1.5-fold to 9.3-fold; P <.001) by itraconazole. The suppression of cortisol production after inhalation of budesonide was significantly increased by itraconazole as compared with placebo, as shown by a 43% reduction in the area under the plasma cortisol concentration-time curve from 0.5 to 10 hours (P <.001) and a 12% decrease in the cortisol concentration measured 23 hours after administration of budesonide, at 8 am (P <.05).


CONCLUSIONS
Itraconazole markedly increased systemic exposure to inhaled budesonide, probably by inhibiting the cytochrome P4503A4-mediated metabolism of budesonide during both the first-pass and the elimination phases. This interaction resulted in enhanced systemic effects of budesonide, as shown by suppression of cortisol production. Long-term coadministration of budesonide and a potent CYP3A4 inhibitor may be associated with an increased risk of adverse effects of budesonide.
Raaska
Kari
K
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Niemi
Mikko
M
Neuvonen
Mikko
M
Neuvonen
Pertti J
PJ
Kivistö
Kari T
KT
D000280:Administration, Inhalation; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D019819:Budesonide / Q000097:blood* / Q000494:pharmacology; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004311:Double-Blind Method; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D017964:Itraconazole / Q000097:blood / Q000494:pharmacology*; D008297:Male; D018709:Statistics, Nonparametric
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017964:Itraconazole; D019819:Budesonide; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006854:Hydrocortisone