Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine.
OBJECTIVE
To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy 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 period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10.


RESULTS
Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70-142%) but not DCL concentrations (6% increase; 1-11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events.


CONCLUSIONS
Loratadine 10 mg daily was devoid of any effects on electrocardiographic 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.
Kosoglou
T
T
Departments of Clinical Pharmacology, Drug Metabolism and Pharmacokinetics and Biostatistics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. teddy.kosoglou@spcorp.com
Salfi
M
M
Lim
J M
JM
Batra
V K
VK
Cayen
M N
MN
Affrime
M B
MB
D000328:Adult; D000935:Antifungal Agents / Q000009:adverse effects / Q000494:pharmacology; D002927:Cimetidine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D003257:Consumer Product Safety; D018592:Cross-Over Studies; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D017336:Loratadine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D016037:Single-Blind Method
D000935:Antifungal Agents; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D017336:Loratadine; D002927:Cimetidine; D007654:Ketoconazole