Co‐administration of ketoconazole with H₁‐antagonists ebastine and loratadine in healthy subjects: pharmacokinetic and pharmacodynamic effects

Abstract

AimsTwo studies were conducted to evaluate the effects of coadministration of ketoconazole with two nonsedating antihistamines, ebastine and loratadine, on the QTc interval and on the pharmacokinetics of the antihistamines. MethodsIn both studies healthy male subjects (55 in one study and 62 in the other) were assigned to receive 5 days of antihistamine (ebastine 20 mg qd in one study, and loratadine 10 mg qd in the other) or placebo alone using a predetermined randomization schedule, followed by 8 days of concomitant ketoconazole 450 mg qd/ antihistamine or ketoconazole 400 mg qd/placebo. Serial ECGs and blood sampling for drug analysis were performed at baseline and on study days 5 (at the end of monotherapy) and 13 (at the end of combination therapy). QT intervals were corrected for heart rate using the formula QTc = QT/RR a with special emphasis on individualized a values derived from each subject's own QT/RR relationship at baseline. ResultsNo significant changes in QTc interval from baseline were observed after 5 days administration of ebastine, loratadine or placebo. Ketoconazole/placebo increased the mean QTc (95% CI) by 6.96 (3.31-10.62) ms in the ebastine study and by 7.52 (4.15-10.89) ms in the loratadine study. Mean QTc was statistically significantly increased during both ebastine/ketoconazole administration (12.21 ms; 7.39-17.03 ms) and loratadine/ketoconazole administration (10.68 ms; 6.15-15.21 ms) but these changes were not statistically significantly different from the increases seen with placebo/ketoconazole (6.96 ms; 3.31-10.62 ms), P = 0.08 ebastine study, (7.52 ms; 4.15-10.89 ms), P = 0.26 loratadine study). After the addition of ketoconazole, the mean area under the plasma concentration-time curve (AUC) for ebastine increased by 42.5 fold, and that of its metabolite carebastine by 1.4 fold. The mean AUC for loratadine increased by 4.5 fold and that of its metabolite desloratadine by 1.9 fold following administration of ketoconazole. No subjects were withdrawn because of ECG changes or drug-related adverse events. ConclusionsKetoconazole altered the pharmacokinetic profiles of both ebastine and loratadine although the effect was greater for the former drug. The coadministration of ebastine with ketoconazole resulted in a non significant mean increase of 5.25 ms ( -0.65 to Co-administration of ketoconazole with H1-antagonists ebastine and loratadine Br J Clin Pharmacol 59 :3 347

Characterization of Ebastine, Hydroxyebastine, and Carebastine Metabolism by Human Liver Microsomes and Expressed Cytochrome P450 Enzymes: Major Roles for CYP2J2 and CYP3A

“…The C max value of hydroxyebastine, the major metabolite of ebastine in vitro, was approximately 50-fold lower than that of carebastine in vivo (Kang et al, 2004). A recent study by Chaikin et al (2005) has reported that ketoconazole, a potent inhibitor of CYP3A4-mediated metabolism, decreases the clearance of ebastine, leading to an accumulation of the ebastine, with little effect on the pharmacokinetics of carebastine. However, since they did not measure the change of the intermediate metabolite, hydroxyebastine, it is still open to question which P450 isoforms may contribute to the formation of carebastine.…”

Ebastine in allergic rhinitis and chronic idiopathic urticaria

“…In healthy volunteers receiving ebastine 20 mg once-daily, the addition of ketoconazole 400 mg once-daily for 8 days increased AUC, C max and t max of carebastine by 1.4-, 1.1-and 3.4-fold, respectively (all P < 0.05), while these parameters increased 43-, 16-and twofold for ebastine (all P < 0.05). Carebastine t ½ increased from 25 to 81 h. Importantly, the greater exposure to ebastine and its main metabolite resulting from co-administration with ketoconazole was not accompanied by a significant increase in cardiac repolarization as measured by QTc interval (35). Co-administration of erythromycin with ebastine also altered the pharmacokinetics of ebastine and carebastine.…”

“…In addition, co-administration of either of these agents with ebastine increases the plasma concentration of ebastine (see Pharmacokinetic properties). In a study in healthy volunteers, co-administration of ebastine 20 mg/day with ketoconazole 400 mg/day for 8 days led to a statistically significant increase in QTc interval of 12 ms compared with baseline (P < 0.00001); however, this increase was not significantly different from that seen with ketoconazole alone (7 ms) (35). No participant experienced a QTc interval >500 ms.…”

“…Co-administration of ketoconazole with ebastine led to significant alterations in the pharmacokinetics of both ebastine and carebastine (35). In healthy volunteers receiving ebastine 20 mg once-daily, the addition of ketoconazole 400 mg once-daily for 8 days increased AUC, C max and t max of carebastine by 1.4-, 1.1-and 3.4-fold, respectively (all P < 0.05), while these parameters increased 43-, 16-and twofold for ebastine (all P < 0.05).…”

How to Assess QT Prolongation in Clinical Studies-Implications of the ICH E14 Guidance Document

“…Most often, this is achieved by including a treatment period in which subjects are dosed with a drug that mildly prolongs the QTc interval, such as a low-dose ibutilide infusion or oral moxifloxacin, a fluoroquinolone antibiotic 13,[23][24][25]. Ketoconazole, a potent hERG blocker 26), is less well characterized clinically, but has also recently been used as a positive control with an effect size that seems to meet the E14 criteria 23,27). The positive control is meant to validate the study's sensitivity, i.e.…”