He Y-L, Yamaguchi M, Ito H, Terao S, Sekiguchi K
Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA.
Int J Clin Pharmacol Ther. 2010 Sep;48(9):582-95. doi: 10.5414/cpp48582.
To assess the pharmacokinetics, pharmacodynamics and safety of vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), in Japanese patients with Type 2 diabetes.
In this randomized, double-blind, placebo-controlled, parallel-group study, 62 Japanese patients with Type 2 diabetes received vildagliptin 10 mg, 25 mg or 50 mg twice daily for 7 days. Blood samples were collected for the determination of plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin and glucagon.
Exposure to vildagliptin (area under the plasma concentration-time curve from 0 to 12 h (AUC0-12h) and the maximum plasma concentration (Cmax)) increased in an approximately dose-proportional manner, and no accumulation was observed following multiple doses of vildagliptin (accumulation factor 1.00 - 1.02). DPP-4 activity was completely inhibited for varying durations by all doses of vildagliptin; the duration of complete DPP-4 inhibition was dose-dependent. DPP-4 inhibition after vildagliptin 50 mg twice daily remained > 80% throughout the 24-h period. Vildagliptin treatment led to a dose-dependent increase in plasma active GLP-1 levels; the overall increases (area under the effect-time course from 0 to 8 h, AUE0-8h) after 7 days' treatment were 1.5-, 1.7-, and 1.8-fold with vildagliptin 10 mg, 25 mg and 50 mg twice daily, respectively (all p < 0.0001 vs. placebo). Postprandial plasma glucose during the 4-h period after breakfast was significantly reduced with the 10, 25 and 50 mg vildagliptin doses by 50.3, 92.2 and 69.5 mg·h/dl, respectively. Insulin levels remained unchanged in the context of reduced glucose levels at all doses studied.
Vildagliptin demonstrated similar pharmacokinetic and pharmacodynamic effects in Japanese patients to those observed previously in non-Japanese patients with Type 2 diabetes.
评估强效、选择性二肽基肽酶IV（DPP-4）抑制剂维格列汀在日本2型糖尿病患者中的药代动力学、药效学及安全性。
在这项随机、双盲、安慰剂对照、平行组研究中，62例日本2型糖尿病患者每日两次接受10 mg、25 mg或50 mg维格列汀治疗，共7天。采集血样以测定维格列汀、DPP-4、胰高血糖素样肽-1（GLP-1）、葡萄糖、胰岛素和胰高血糖素的血浆浓度。
维格列汀的暴露量（0至12小时血浆浓度-时间曲线下面积（AUC0-12h）及最大血浆浓度（Cmax））以近似剂量比例的方式增加，多次给药后未观察到蓄积（蓄积因子1.00 - 1.02）。所有剂量的维格列汀均在不同持续时间内完全抑制DPP-4活性；完全抑制DPP-4的持续时间呈剂量依赖性。每日两次50 mg维格列汀给药后，在整个24小时期间DPP-4抑制率仍>80%。维格列汀治疗导致血浆活性GLP-1水平呈剂量依赖性增加；每日两次10 mg、25 mg和50 mg维格列汀治疗7天后的总体增加量（0至8小时效应-时间曲线下面积，AUE0-8h）分别为1.5倍、1.7倍和1.8倍（与安慰剂相比，均p < 0.0001）。早餐后4小时期间，10 mg、25 mg和50 mg维格列汀剂量分别使餐后血浆葡萄糖显著降低50.3、92.2和69.5 mg·h/dl。在所研究的所有剂量下，胰岛素水平在血糖水平降低的情况下保持不变。
维格列汀在日本患者中表现出与先前在非日本2型糖尿病患者中观察到的相似的药代动力学和药效学效应。
