Effect of age and gender on the pharmacokinetics of ebastine after single and repeated dosing in healthy subjects

Objectives: Ebastine is a potent and selective H1-receptor antagonist indic ated for allergic rhinitis which undergoes extensive first pass metabolism by CYP3A4 to form an active metabolite, carebastine. The purpose of the stu dy was to determine age- and gender-related differences in the pharmacokine tics of ebastine and carebastine. Methods: The upper recommemded oral dose of 20 mg once daily was administered to 12 healthy young (22 to 38 years) a nd 12 healthy elderly (50 to 92 years; 8 in and 4 f) subjects for 5 days. P lasma concentrations of ebastine and carebastine were determined for 24 hou rs following the initial dose on Day 1 and for 72 hours following the dose on Day 5 using a sensitive LC/MS/MS assay. The minimum quantifiable limit ( MQL) for the assay was 0.05 ng/ml and 1.0 ng/ml for ebastine and carebastin e, respectively. Results: Mean area under the curve and C-max values on Day 1 and Day 5 were similar for ebastine but approximately doubled for careba stine due to its longer half-life. Mean carebastine concentrations were app roximately 10 to 20 fold higher than mean ebastine concentrations. For youn g subjects, the mean (%CV) ebastine t(1/2) was 5.76 (28.47)h and 20.38 (46. 19)h on Day 1 and Day 5, respectively. Similarily, for young subjects, the mean (%CV) for carebastine t(1/2) was 7.03 (23.21)h and 26.12 (23.39) h on Day 1 and Day 5, respectively. This apparent prolongation t(1/),(2) was pro bably due to lack of proper estimation of terminal half-life on Day 1 as fe wer samples were collected for a shorter duration on Day 1. Using a multico mparison test for Cmin values, it was determined that steady state conditio ns were achieved by Day 5 for both age groups for ebastine and in young sub jects for carebastine. The variability in ebastine pharmacokinetic paramete rs was higher than carebastine. A 50% increase in ebastine AUC(0-24) and C- max values in elderly subjects, with no changes in t(1/2) could be explaine d by either increased absorption of ebastine in elderly subjects or due to a decrease in First pass metabolism. As ebastine shows a high first-pass ef fect, even a small change in this first pass can cause large changes in pla sma exposure. The ebastine pharmacokinetic parameters for elderly subjects in this study lie between the values reported in young subjects in earlier studies. Hence, the apparent age-related pharmacokinetic difference for eba stine is probably due to the inherent variability in ebastine pharmacokinet ics. There were no gender-related differences in either young or elderly su bjects for mean AUC, Cmax, t(max) and t(1/2) ebastine and carebastine value s. Ebastine was absorbed rapidly with a median t(max) of 1.25 to 2.25 h for both healthy young and elderly males and females on Day 1 and Day 5. There was a delayed appearance of carebastine as expressed by median t(max) of 4 .0 to 5.0 h, which did not change with age, gender or repeated administrati on. There were no clinically relevant differences between the groups of sub jects with respect to adverse events or safety parameters. Conclusions: Thu s, ebastine can be safely administered to elderly subjects vith no clinical ly important age- or gender related differences in the pharmacokinetics of ebastine/carebastine.