Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: A randomized, placebo-controlled, parallel-group study

Background: Significant cardiac toxicity has been associated with some olde r antihistamines (eg, terfenadine and astemizole) when their plasma concent rations are increased. There is thus a need for a thorough assessment of th e cardiac safety of newer antihistamine compounds. Objective: This study was undertaken to assess the effects of coadministrat ion of desloratadine or fexofenadine with azithromycin on pharmacokinetic p arameters, tolerability, and electrocardiographic (ECG) findings. Methods: Healthy volunteers aged 19 to 46 years participated in this random ized, placebo-controlled, parallel-group. third-party-blind, multiple-dose study. Subjects received desloratadine 5 mg once daily, fexofenadine 60 mg twice daily, or placebo for 7 days. An azithromycin loading dose (500 mg) f ollowed by azithromycin 250 mg once daily for 4 days was administered conco mitantly starting on day 3. Group 1 received desloratadine and azithromycin , group 2 received desloratadine and placebo, group 3 received placebo and azithromycin, group 4 received fexofenadine and azithromycin, and group 5 r eceived fexofenadine and placebo. Results: The results of the pharmacokinetic analysis revealed little change in mean maximum concentration (C) and area under the concentration-time cu rve (AUC) values max for desloratadine with concomitant administration of a zithromycin: C-max ratio, 115% (90% CI, 92-144); AUG, ratio 105% (90% CI, 8 2-134). The corresponding ratios for 3-hydroxydesloratadine were 115% (90% CI, 98-136) and 104% (90% CI, 88-122), respectively. A substantial increase was observed in mean C-max and AUC values for fexofenadine when administer ed with azithromycin: C-max ratio, 169% (90% CI, 120-237)1 AUC ratio, 167% (90% CI, 122-229). Compared with the group receiving desloratadine and azit hromycin, subjects receiving fexofenadine and azithromycin also displayed g reater variability in pharmacokinetic parameters for the antihistamine. Mea n C and AUC max values of azithromycin were slightly higher when administer ed with desloratadine (C-max ratio, 131% [90% CI, 92-1873, AUC ratio, 112% [90% CI, 83-153]) but were lower when given in combination with fexofenadin e (C-max ratio, 87% [90% CI, 61-124]: AUC ratio, 88% [90% CI. 65-120]). The most common adverse event for all regimens was headache, reported in 20 (2 2%) subjects. All combinations of desloratadine or fexofenadine with and wi thout azithromycin were well tolerated, and no statistically significant ch anges in PR, QT. or QT(c) interval, QRS complex, or ventricular rate were o bserved. Conclusions: Small increases (<15%) in mean pharmacokinetics of desloratadi ne were observed with coadministration of azithromycin. By contrast, peak f exofenadine concentrations were increased by 69% and the AUC was increased by 67% in the presence of the azalide antibiotic. Based on the reported adv erse-events profile and the absence of changes in ECG parameters, the combi nation of desloratadine and azithromycin was well tolerated. This study sug gests that desloratadine has a more favorable drug-interaction potential th an does fexofenadine.