Rohatagi S, Gillen M, Aubeneau M, Jan C, Pandit B, Jensen B K, Rhodes G
Department of Drug Metabolism and Pharmacokinetics, Aventis Pharmaceutical, Collegeville, PA, USA.
Int J Clin Pharmacol Ther. 2001 Mar;39(3):126-34. doi: 10.5414/cpp39126.
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.
The upper recommended oral dose of 20 mg once daily was administered to 12 healthy young (22 to 38 years) and 12 healthy elderly (50 to 92 years; 8 m and 4 f) subjects for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours 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 carebastine, respectively.
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.
Thus, ebastine can be safely administered to elderly subjects with no clinically important age- or gender related differences in the pharmacokinetics of ebastine/carebastine.
依巴斯汀是一种强效、选择性H1受体拮抗剂，用于治疗过敏性鼻炎，它经CYP3A4广泛首过代谢形成活性代谢产物卡瑞巴斯汀。本研究的目的是确定依巴斯汀和卡瑞巴斯汀药代动力学的年龄和性别差异。
将每日一次20mg的最高推荐口服剂量给予12名健康年轻受试者（22至38岁）和12名健康老年受试者（50至92岁；8名男性和4名女性），持续5天。在第1天首次给药后24小时以及第5天给药后72小时，使用灵敏的液相色谱/串联质谱分析法测定依巴斯汀和卡瑞巴斯汀的血浆浓度。该分析方法对依巴斯汀和卡瑞巴斯汀的最低定量限分别为0.05ng/ml和1.0ng/ml。
依巴斯汀在第1天和第5天的曲线下平均面积和Cmax值相似，但卡瑞巴斯汀由于半衰期较长，其值约增加了一倍。卡瑞巴斯汀的平均浓度比依巴斯汀的平均浓度高约10至20倍。对于年轻受试者，依巴斯汀在第1天和第5天的平均（%CV）t(1/2)分别为5.76（28.47）小时和20.38（46.19）小时。同样，对于年轻受试者，卡瑞巴斯汀在第1天和第
