Effect of azole antifungals ketoconazole and fluconazole on the pharmacokinetics of dexloxiglumide

Aims Dexloxiglumide is a new CCK1 receptor antagonist under investigation for treatment of functional gastrointestinal disorders and is metabolized by CYP3A4 and CYP2C9. The objectives of these two separate randomized, two-period, two-treatment crossover studies were to investigate the effects of steady-state ketoconazole, a model CYP3A4 inhibitor (Study 1), and steady-state fluconazole, a model CYP2C9 inhibitor (Study 2), on the pharmacokinetics of dexloxiglumide in healthy subjects. Methods Plasma samples were analysed for dexloxiglumide and its primary metabolites: O-demethyl dexloxiglumide (ODM; Study 1 and 2) and dexloxiglumide carboxylic acid (DCA; Study 2). Results Following ketoconazole coadministration, dexloxiglumide C-max increased by 32% (90% confidence intervals (CI) 112-154), with unchanged ODM C-max; AUC of dexloxiglumide and ODM increased by 36% (90% CI 124-140 and 128-142, respectively). No changes were observed in dexloxiglumide or ODM t(1/2). Fluconazole coadministration caused a 77% increase (90% CI 154-204) in dexloxiglumide C-max, no change in ODM C-max and a 32% decrease (90% CI 62-75) in DCA C-max. Fluconazole coadministration resulted in a 2.5-fold increase (90% CI 235-267) in dexloxiglumide AUC, 40% increase (90% CI 136-156) in ODM AUC and an 18% decrease (90% CI 82-94) in DCA AUC. The t(1/2) of all three analytes increased by approximately 2-fold with fluconazole coadministration (P-value < 0.05). Conclusions Ketoconazole caused a minimal increase while fluconazole caused a moderate increase in dexloxiglumide systemic exposure with no change in the adverse event profile of dexloxiglumide.