阿格列汀与食物、二甲双胍或西咪替丁联用时的药代动力学：一项在健康受试者中进行的两阶段交叉研究。

Pharmacokinetics of alogliptin when administered with food, metformin, or cimetidine: a two-phase, crossover study in healthy subjects.

作者信息

Karim A, Covington P, Christopher R, Davenport M, Fleck P, Li X, Wann E, Mekki Q

机构信息

Takeda Global Research & Development Center, Inc., 675 North Field Drive, Lake Forest, IL 60045, USA.

出版信息

Int J Clin Pharmacol Ther. 2010 Jan;48(1):46-58. doi: 10.5414/cpp48046.

DOI:10.5414/cpp48046

PMID:20040339

Abstract

OBJECTIVE

The dipeptidyl peptidase-4 inhibitor alogliptin, under development for treatment of Type 2 diabetes, primarily is excreted renally. This study investigated (1) the effect of food on alogliptin pharmacokinetics and tolerability and (2) pharmacokinetic interactions between alogliptin and metformin or cimetidine and tolerability of alogliptin when administered with either drug.

METHODS

This randomized, open-label, two-phase, crossover study recruited healthy adults. In the single-dose phase, 36 subjects received an oral dose of alogliptin 100 mg under fed or fasted conditions. In the multiple-dose phase, subjects in one arm (n = 17) received 6 days each of alogliptin 100 mg once daily (q.d.), metformin 1,000 mg twice daily (b.i.d), and alogliptin q.d. + metformin b.i.d; subjects in the other arm (n = 18) received 6 days each of alogliptin 100 mg q.d., cimetidine 400 mg q.d., and alogliptin q.d. + cimetidine b.i.d. Pharmacokinetic parameters were determined after the last dose in each period. Tolerability was assessed through adverse events and clinical findings.

RESULTS

Food had no effect on alogliptin area under the concentration-time curve (AUC) from 0 h to infinity and a small, clinically insignificant effect on maximum plasma concentration (C(max)) (fed/fasted least squares (LS) geometric mean ratio, 0.856; 90% confidence interval (CI), 0.798 - 0.917). Metformin and cimetidine did not affect alogliptin pharmacokinetics. Alogliptin had no effect on metformin C(max) and a small, clinically insignificant effect on AUC over the dosing interval ((alogliptin + metformin)/metformin LS geometric mean ratio, 1.19; 90% CI, 1.095 - 1.291). Alogliptin did not affect cimetidine pharmacokinetics. Alogliptin tolerability was similar under all conditions.

CONCLUSION

Alogliptin can be administered without regard to meals and with metformin or cimetidine without the need for dose adjustment.

摘要

目的

正在研发用于治疗2型糖尿病的二肽基肽酶-4抑制剂阿格列汀主要经肾脏排泄。本研究调查了：（1）食物对阿格列汀药代动力学和耐受性的影响；（2）阿格列汀与二甲双胍或西咪替丁之间的药代动力学相互作用，以及与任一药物联用时阿格列汀的耐受性。

方法

这项随机、开放标签、两阶段、交叉研究招募了健康成年人。在单剂量阶段，36名受试者在进食或禁食条件下口服100mg阿格列汀。在多剂量阶段，一组受试者（n = 17）每天接受一次100mg阿格列汀、每天两次1000mg二甲双胍，以及阿格列汀每日一次 + 二甲双胍每日两次，各服用6天；另一组受试者（n = 18）每天接受一次100mg阿格列汀、每天一次400mg西咪替丁，以及阿格列汀每日一次 + 西咪替丁每日两次，各服用6天。在每个阶段的最后一剂后测定药代动力学参数。通过不良事件和临床检查评估耐受性。

结果

食物对阿格列汀从0小时至无穷大的浓度-时间曲线下面积（AUC）无影响，对最大血浆浓度（C(max)）有微小的、临床意义不显著的影响（进食/禁食最小二乘法（LS）几何平均比值为0.856；90%置信区间（CI）为0.798 - 0.917）。二甲双胍和西咪替丁不影响阿格列汀的药代动力学。阿格列汀对二甲双胍的C(max)无影响，对给药间隔期间的AUC有微小的、临床意义不显著的影响（（阿格列汀 + 二甲双胍）/二甲双胍LS几何平均比值为1.19；90%CI为1.095 - 1.291）。阿格列汀不影响西咪替丁的药代动力学。在所有条件下，阿格列汀的耐受性相似。