Lack of Effect of Erythromycin and Ketoconazole on the Pharmacokinetics and Pharmacodynamics of Steady-State Intranasal Levocabastine

• Published in: Journal of clinical pharmacology 1999-01, Vol.39 (1), p.76-85
• Main Authors: Pesco-Koplowitz, Luana, Hassell, Alan, Lee, Peter, Zhou, Honghui, Hall, Nancy, Wiesinger, Barbara, Mechlinski, Witold, Grover, Matthew, Hunt, Thomas, Smith, Randall, Travers, Suzanne
• Format: Article
• Language: English
• Subjects: Administration, Intranasal; Adolescent; Adult; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacology; Anti-Infective Agents - pharmacology; Area Under Curve; Biological and medical sciences; Biological Availability; Bradycardia - chemically induced; Cross-Over Studies; Drug Interactions; Electrocardiography - drug effects; Erythromycin - adverse effects; Erythromycin - pharmacology; Headache - chemically induced; Heart Block - chemically induced; Histamine and antagonists. Allergy; Histamine H1 Antagonists - adverse effects; Histamine H1 Antagonists - pharmacokinetics; Humans; Ketoconazole - adverse effects; Ketoconazole - pharmacology; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Piperidines - adverse effects; Piperidines - pharmacokinetics; Rhinitis - chemically induced; Time Factors; Virus Diseases - chemically induced
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/00912709922007589

The single‐dose effects of the cytochrome P‐450 inhibitors erythromycin and ketoconazole on the steady‐state pharmacokinetics and electrocardiographic repolarization pharmacodynamics of intranasal levocabastine, a potent and selective H1‐receptor antagonist, were evaluated in healthy young male subjects. Two randomized, open‐label, placebo‐controlled, two‐way crossover studies were performed. Levocabastine nasal spray was administered as two sprays per nostril (0.05 mg/spray) twice daily (for a total daily dose of 0.4 mg) for 6 days. On Day 7, a single dose of 0.2 mg was administered followed immediately by a single dose of either oral placebo, erythromycin 333 mg, or ketoconazole 200 mg. In all treatment groups, levocabastine was rapidly absorbed, with peak plasma concentrations reached at approximately 3 hours in the erythromycin study and 2.8 hours in the ketoconazole study. The mean terminal half‐life was approximately 45 and 44 hours, respectively. In both studies, mean steady‐state plasma concentrations and pharmacokinetics of levocabastine following the single doses of erythromycin or ketoconazole were not significantly different from corresponding values seen with the concomitant administration of the placebo. No clinically significant mean changes from baseline in QT or QTc (QT corrected for heart rate) intervals occurred in any of the treatment groups, and none of the subjects in either study experienced abnormally prolonged QTc intervals. Intranasal levocabastine was well tolerated, with no difference in the incidence of adverse events between treatment groups in either study; adverse events were generally mild in severity. Since levocabastine undergoes only minimal hepatic metabolism and is not a substrate for or an inhibitor of cytochrome P‐450, the likelihood of systemic drug interactions with drugs affecting the cytochrome P‐450 system is minimal.