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

Clin Ther. 2008 Sep;30(9):1639-50. doi: 10.1016/j.clinthera.2008.09.002.


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-tau) 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-tau for desloratadine and 109 (90% CI, 103-115) for Cmax,ss and 104 (90% CI, 100-108) for AUC0-tau 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 interval used for comparing bioavailability of the drugs. A total of 5 subjects reported 9 AEs; 5 of these were thought to be related to the drug administration and all were categorized as mild or moderate. The reported AEs were somnolence (1/24 in the rupatadine group and 1/24 in the rupatadine plus azithromycin group), diarrhea (1/24 in the rupatadine plus azithromycin group), and gastric discomfort (2/24 in the rupatadine plus azithromycin group). Four AEs were considered not to be related (2 episodes of headache, 1 anemia, 1 cheilitis). All were resolved spontaneously. No serious AEs were reported.

Conclusions: The results of this study in these healthy volunteers found no significant differences in pharmacokinetic parameters other than Cmax,ss of 3-hydroxydesloratadine between rupatadine 10 mg administered alone or with azithromycin 500 mg on day 2 and 250 mg from day 3 to day 6. The administration of rupatadine compared with rupatadine plus azithromycin met the regulatory definition of bioequivalence in terms of exposure and rate parameters; however, Cmax,ss of rupatadine was outside the conventional confidence interval.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / adverse effects
  • Anti-Bacterial Agents / pharmacology*
  • Area Under Curve
  • Azithromycin / administration & dosage
  • Azithromycin / adverse effects
  • Azithromycin / pharmacology*
  • Chromatography, High Pressure Liquid
  • Confidence Intervals
  • Cross-Over Studies
  • Cyproheptadine / administration & dosage
  • Cyproheptadine / adverse effects
  • Cyproheptadine / analogs & derivatives*
  • Cyproheptadine / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Female
  • Histamine H1 Antagonists / administration & dosage
  • Histamine H1 Antagonists / adverse effects
  • Histamine H1 Antagonists / pharmacokinetics*
  • Humans
  • Loratadine / administration & dosage
  • Loratadine / adverse effects
  • Loratadine / analogs & derivatives
  • Loratadine / blood
  • Loratadine / pharmacokinetics*
  • Male
  • Safety
  • Therapeutic Equivalency


  • Anti-Bacterial Agents
  • Histamine H1 Antagonists
  • rupatadine
  • Cyproheptadine
  • 3-hydroxydesloratadine
  • Loratadine
  • Azithromycin
  • desloratadine