Lack of effect of azelastine and ketoconazole coadministration on electrocardiographic parameters in healthy volunteers

J Clin Pharmacol. 1997 Nov;37(11):1065-72. doi: 10.1002/j.1552-4604.1997.tb04289.x.


Azelastine, an antihistamine with additional pharmacologic properties, was evaluated for a possible influence on pharmacokinetic and electrocardiographic parameters due to its coadministration with CYP3A4 inhibitor ketoconazole (200 mg every 12 hrs). Twelve volunteers entered this three-period, open-label study. Electrocardiographic parameters (PR, QRS and QTc intervals and U-wave morphology) were monitored after 14 days of azelastine HCl (4.4 mg every 12 hrs), after 7 days of either azelastine/ketoconazole or azelastine/placebo, and after a 21-day washout period, which was then followed by a 7-day administration of ketoconazole alone. None of the treatments resulted in meaningful alterations of electrocardiographic variables. Pharmacokinetic parameters could not be estimated because ketoconazole metabolites interfered with azelastine assay procedures. In vitro tests with human liver microsomes were used to characterize azelastine's inhibition spectrum. Azelastine did not inhibit CYP3A4 activity but it did inhibit CYP2D6 and CYP2C19 activity with Ki values exceeding maximum plasma concentration by 120 to 800-fold. Therefore, in vitro tests and the absence of electrocardiographic effects suggests azelastine can be safely administered with CYP3A4 inhibitors.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial

MeSH terms

  • Adult
  • Antifungal Agents / metabolism
  • Antifungal Agents / pharmacokinetics
  • Antifungal Agents / pharmacology*
  • Area Under Curve
  • Cytochrome P-450 Enzyme System / metabolism
  • Double-Blind Method
  • Electrocardiography / drug effects*
  • Heart Rate / drug effects*
  • Histamine H1 Antagonists / metabolism
  • Histamine H1 Antagonists / pharmacokinetics
  • Histamine H1 Antagonists / pharmacology*
  • Humans
  • Ketoconazole / metabolism
  • Ketoconazole / pharmacokinetics
  • Ketoconazole / pharmacology*
  • Male
  • Phthalazines / metabolism
  • Phthalazines / pharmacokinetics
  • Phthalazines / pharmacology*


  • Antifungal Agents
  • Histamine H1 Antagonists
  • Phthalazines
  • Cytochrome P-450 Enzyme System
  • Ketoconazole
  • azelastine