Ebastine is a potent and selective H1-receptor antagonist indicated for
allergic rhinitis which undergoes extensive first pass metabolism by
CYP3A4 to form an active metabolite,
carebastine. The purpose of the study was to determine age- and gender-related differences in the pharmacokinetics of
ebastine and
carebastine.
METHODS: Mean area under the curve and Cmax values on Day 1 and Day 5 were similar for
ebastine but approximately doubled for
carebastine due to its longer half-life. Mean
carebastine concentrations were approximately 10 to 20 fold higher than mean
ebastine concentrations. For young 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 of t(1/2) was probably due to lack of proper estimation of terminal half-life on Day 1 as fewer samples were collected for a shorter duration on Day 1. Using a multicomparison test for Cmin values, it was determined that steady state conditions were achieved by Day 5 for both age groups for
ebastine and in young subjects for
carebastine. The variability in
ebastine pharmacokinetic parameters was higher than
carebastine. A 50% increase in
ebastine AUC(0-24) and Cmax values in elderly subjects, with no changes in t(1/2), could be explained 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 effect, even a small change in this first pass can cause large changes in plasma 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
ebastine is probably due to the inherent variability in
ebastine pharmacokinetics. There were no gender-related differences in either young or elderly subjects for mean AUC, Cmax, tmax and t(1/2)
ebastine and
carebastine values.
Ebastine was absorbed rapidly with a median tmax 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 tmax of 4.0 to 5.0 h, which did not change with age, gender or repeated administration. There were no clinically relevant differences between the groups of subjects with respect to adverse events or safety parameters.
CONCLUSIONS: