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

Abstract

Aims 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 signi®cantly 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 signi®cantly 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 signi®cant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety pro®le 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 signi®cant 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.

Effects of Hydrocortisone on the Pharmacokinetics of Loratadine after Oral and Intravenous Loratadine Administration to Rats

“…The enhanced bioavailability of loratidine may have been due to inhibition of both CYP 3A4-mediated metabolism and P-gp in the intestine and/or liver by the presence of hydrocortisone. This result was consistent with previous studies showing that single oral administration of cimetidine, clarithromycin or ketoconazole significantly increased the AUC and Cmax of loratadine in rats by inhibition of CYP3A4 (Carr et al, 1998;Kosoglou et al, 2000). Overall, the presence of hydrocortisone significantly enhances the oral bioavailability of loratadine by increasing the intestinal absorption and reducing the first-pass metabolism of loratadine.…”

“…Previous reports have indicated pharmacokinetic interactions between loratadine and other drugs, such as cimetidine, clarithromycin and ketoconazole (Carr et al, 1998;Kosoglou et al, 2000). These significantly increased the AUC and Cmax of loratadine in rats by inhibition of CYP3A4 and P-gp.…”

Effects of Curcumin on the Pharmacokinetics of Loratadine in Rats: Possible Role of CYP3A4 and P-glycoprotein Inhibition by Curcumin

“…The enhanced oral bioavailability of loratadine contributed to the competitive inhibition of loratadine metabolism by CYP 3A4 both in the liver and intestine. This result was consistent with previous studies showing that a single oral administration of cimeti- www.biomolther.org dine, clarithromycin and ketoconazole signifi cantly increased the AUC and C max of loratadine in rats through inhibition of CYP3A4 (Carr et al, 1998;Kosoglou et al, 2000). These results are coincident with previous studies, in which CYP3A9 expressed in rat is corresponds to the ortholog of CYP3A4 in human (Kelly et al, 1999).…”

EFFECT OFCYP2D6*10ALLELE ON THE PHARMACOKINETICS OF LORATADINE IN CHINESE SUBJECTS

“…Previous studies showed that CYP3A4 inhibitors such as clarithromycin (Carr et al, 1998), erythromycin (Brannan et al, 1995), and ketoconazole (Kosoglou et al, 2000) significantly increased the plasma concentrations of loratadine. These data indirectly suggested a significant in vivo involvement of CYP3A4 in loratadine metabolism.…”