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

• Published in: Clinical therapeutics 2001-03, Vol.23 (3), p.451-466
• Main Authors: Gupta, Samir, Banfield, Christopher, Kantesaria, Bhavna, Marino, Mark, Clement, Robert, Affrime, Melton, Batra, Vijay
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Anti-Bacterial Agents - administration & dosage; azithromycin; Azithromycin - administration & dosage; Azithromycin - adverse effects; Azithromycin - pharmacokinetics; Biological and medical sciences; desloratadine; Drug toxicity and drugs side effects treatment; electrocardiographic findings; Electrocardiography - drug effects; Female; fexofenadine; Histamine H1 Antagonists - administration & dosage; Humans; Loratadine - administration & dosage; Loratadine - adverse effects; Loratadine - analogs & derivatives; Loratadine - pharmacokinetics; Male; Medical sciences; Middle Aged; pharmacokinetics; Pharmacology. Drug treatments; Terfenadine - administration & dosage; Terfenadine - adverse effects; Terfenadine - analogs & derivatives; Terfenadine - pharmacokinetics; Toxicity: cardiovascular system
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/S0149-2918(01)80049-7

Background: Significant cardiac toxicity has been associated with some older antihistamines (eg, terfenadine and astemizole) when their plasma concentrations are increased. There is thus a need for a thorough assessment of the cardiac safety of newer antihistamine compounds. Objective: This study was undertaken to assess the effects of coadministration of desloratadine or fexofenadine with azithromycin on pharmacokinetic parameters, tolerability, and electrocardiographic (ECG) findings. Methods: Healthy volunteers aged 19 to 46 years participated in this randomized, 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) followed by azithromycin 250 mg once daily for 4 days was administered concomitantly 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 received fexofenadine and placebo. Results: The results of the pharmacokinetic analysis revealed little change in mean maximum concentration (C max) and area under the concentration-time curve (AUC) values for desloratadine with concomitant administration of azithromycin: C max ratio, 115% (90% CI, 92–144); AUC, ratio 105% (90% CI, 82–134). 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 administered with azithromycin: C max ratio, 169% (90% CI, 120–237); AUC ratio, 167% (90% CI, 122–229). Compared with the group receiving desloratadine and azithromycin, subjects receiving fexofenadine and azithromycin also displayed greater variability in pharmacokinetic parameters for the antihistamine. Mean C max and AUC values of azithromycin were slightly higher when administered with desloratadine (C max ratio, 131% [90% CI, 92–187]; AUC ratio, 112% [90% CI, 83–153]) but were lower when given in combination with fexofenadine (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 (22%) subjects. All combinations of desloratadine or fexofenadine with and without azithromycin were well tolerated, and no statistically significant changes in PR, QT, or QT c