Pharmacokinetic and safety profile of rupatadine when coadministered with azithromycin at steady-state levels: a randomized, open-label, two-way, crossover, Phase I study

Abstract Background: Rupatadine is an oral active antihistamine and platelet-activating factor antagonist indicated for the management of allergic rhinitis and chronic urticaria in Europe. Objective: The purpose of this study was to describe the effect of the concomitant administration of azithromycin and rupatadine on the pharmacokinetics of rupatadine and its metabolites after repeated doses. Methods: This was a multiple-dose, randomized, open-label, 2-way, crossover, Phase I study in which healthy male and female volunteers received rupatadine 10 mg once a day for 6 days either alone or with azithromycin 500 mg on day 2 and 250 mg from day 3 to day 6. Treatments were administered after a fasting period of 10 hours with 240 mL of water, and fasting conditions were kept until 3 hours postmedication. A washout period of at least 21 days between the 2 active periods was observed. Blood samples were collected and plasma concentrations of rupatadine and its metabolites desloratadine and 3-hydroxydesloratadine were determined by liquid chromatography tandem mass spectrometry. Tolerability was based on the recording of adverse events (AEs), physical examination, electrocardiograms, and laboratory screen controls at baseline and the final study visit. Results: Twenty-four healthy volunteers (15 males, 9 females; mean [SD] age, 25.67 [5.58] years; weight, 65.96 [8.57] kg) completed the study. Except for maximum observed concentration during a dosing interval (Cmax,ss ) of 3-hydroxydesloratadine, on average, there were no statistically significant differences in mean plasma concentrations in any of the main pharmacokinetic parameters of rupatadine, desloratadine, and 3-hydroxydesloratadine when administered in combination with azithromycin or alone. The Cmax,ss ratio was 111 (90% CI, 91–136) and area under the plasma concentration-time curve during a dosing interval (AUC0-τ ) ratio had a value of 103 (90% CI, 91–117). The corresponding ratios for the rupatadine metabolites were 109 (90% CI, 100–120) for Cmax,ss and 103 (90% CI, 96–110) for AUC0-τ for desloratadine and 109 (90% CI, 103–115) for Cmax,ss and 104 (90% CI, 100–108) for AUC0-τ for 3-hydroxydesloratadine. Point estimates for Cmax,ss ratios using paired data were 111% for rupatadine, 109% for desloratadine, and 109% for 3-hydroxydesloratadine. The 90% CIs were included in the interval 80% to 125% for desloratadine and 3-hydroxydesloratadine, whereas 90% CI for rupatadine was shifted to the right of the in