The effects of xanthine oxidase inhibition by febuxostat on the pharmacokinetics of theophylline

Abstract

Febuxostat, a non-purine selective xanthine oxidase (XO) inhibitor, may affect the metabolism of theophylline as XO hydroxylates 1-methylxanthine to 1-methyluric acid. The objective of this study was to examine the effects of febuxostat on the pharmacokinetics of theophylline and its metabolites. 24 healthy subjects received febuxostat 80 mg (Regimen A) or matching placebo (Regimen B) daily for 7 days along with a single oral dose of theophylline 400 mg on Day 5 in a double-blind, randomized, cross-over fashion (≥ 7 day washout between periods) followed by collection of plasma and urine samples for 72 h. For Regimens A and B, mean theophylline Cmax values were 4.4 and 4.1 μg/ml, respectively, and mean theophylline AUC0-tlqc was 122.3 and 115.2 μg x h/ml, respectively. The ratios of theophylline Cmax and AUC0-tlqc central values following coadministration with febuxostat or placebo were 1.03 (90% confidence intervals (CIs), 0.917 - 1.149) and 1.04 (90% CI, 0.927 - 1.156). Both 90% CIs fell within the no-effect range of 0.8 and 1.25. Mean excreted amounts in urine for 1-methylxanthine levels were higher in Regimen A vs. B (40.1 vs. 0.1 mg), while 1-methyluric acid levels were lower (3.1 vs. 56.2 mg). Mean excreted amounts of theophylline and other metabolites were comparable between Regimen A and B. No dose adjustment for theophylline is necessary when coadministered with febuxostat 80 mg, as coadministration does not affect the plasma pharmacokinetics of theophylline and neither 1-methylxanthine nor 1-methyluric have any pharmacological effect.