Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine

Aims To evaluate whether ketoconazole or cimetidine alter the pharmacokinet ics of loratadine, or its major metabolite, desloratadine (DCL), or alter t he effects of loratadine or DCL on electrocardiographic repolarization in h ealthy adult volunteers. Methods Two randomized, evaluator-blind, multiple-dose. three-way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout p eriod. The treatments were loratadine alone, cimetidine or ketoconazole alo ne, or loratadine plus cimetidine or ketoconazole. The primary study endpoi nt was the difference in mean QTc intervals from baseline to day 10. In add ition, plasma concentrations of loratadine, DCL, and ketoconazole or cimeti dine were obtained on day 10. Results Concomitant administration of loratadine and ketoconazole significa ntly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of lorat adine alone. Concomitant administration of loratadine and cimetidine signif icantly increased the loratadine plasma concentrations (103% increase; 70-1 42%) but not DCL concentrations (6% increase; 1-11%) compared with administ ration of loratadine alone. Cimetidine or ketoconazole plasma concentration s were unaffected by coadministration with loratadine. Despite increased co ncentrations of loratadine and DCL, there were no statistically significant differences for the primary electro cardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant chan ges in the safety profile of loratadine were observed as assessed by electr ocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratad ine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetid ine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adve rse events. Conclusions Loratadine 10 mg daily was devoid of any effects on electrocard iographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.