肝功能损害对二肽基肽酶IV（DPP-4）抑制剂维格列汀药代动力学的影响。
The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin.
作者信息
He Y-L, Sabo R, Campestrini J, Wang Y, Ligueros-Saylan M, Lasseter K C, Dilzer S C, Howard D, Dole W P
机构信息
Exploratory Development, Novartis Institutes for Biomedical Research, Inc., 400 Technology Square, Building 605, Rm 819, Cambridge, MA 02139-3584, USA.
出版信息
Eur J Clin Pharmacol. 2007 Jul;63(7):677-86. doi: 10.1007/s00228-007-0312-6. Epub 2007 May 8.
OBJECTIVE
Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes mellitus by increasing alpha- and beta-cell responsiveness to glucose. This study investigated the pharmacokinetics of vildagliptin in patients with hepatic impairment compared with healthy subjects.
METHODS
This was an open-label, parallel-group study in patients with mild (n = 6), moderate (n = 6) or severe (n = 4) hepatic impairment and healthy subjects (n = 6). All subjects received a single 100-mg oral dose of vildagliptin, and plasma concentrations of vildagliptin and its main pharmacologically inactive metabolite LAY151 were measured up to 36 h post-dose.
RESULTS
Exposure to vildagliptin (AUC(0-infinity) and C(max)) decreased non-significantly by 20 and 30%, respectively, in patients with mild hepatic impairment [geometric mean ratio (90% CI): AUC(0-infinity), 0.80 (0.60, 1.06), p = 0.192; C(max), 0.70 (0.46, 1.05), p = 0.149]. Exposure to vildagliptin was also decreased non-significantly in patients with moderate hepatic impairment [-8% for AUC(0-infinity), geometric mean ratio (90% CI): 0.92 (0.69, 1.23), p = 0.630; -23% for C(max), geometric mean ratio (90% CI): 0.77 (0.51, 1.17), p = 0.293]. In patients with severe hepatic impairment, C(max) was 6% lower than that in healthy subjects [geometric mean ratio (90% CI): 0.94 (0.59, 1.49), p = 0.285], whereas AUC(0-infinity) was increased by 22% [geometric mean ratio (90% CI): 1.22 (0.89, 1.68), p = 0.816). Across the hepatic impairment groups, LAY151 AUC(0-infinity) and C(max) were increased by 29-84% and 24-63%, respectively, compared with healthy subjects. The single 100-mg oral dose of vildagliptin was well tolerated by patients with hepatic impairment.
CONCLUSIONS
There was no significant difference in exposure to vildagliptin in patients with mild, moderate or severe hepatic impairment; therefore, no dose adjustment of vildagliptin is necessary in patients with hepatic impairment.
目的
维格列汀是一种强效、选择性二肽基肽酶 -IV（DPP -4）抑制剂，通过增强α细胞和β细胞对葡萄糖的反应性来改善2型糖尿病患者的血糖控制。本研究比较了维格列汀在肝功能损害患者与健康受试者中的药代动力学。
方法
这是一项开放标签、平行组研究，纳入轻度（n = 6）、中度（n = 6）或重度（n = 4）肝功能损害患者及健康受试者（n = 6）。所有受试者口服单次100 mg维格列汀，在给药后36小时内测定维格列汀及其主要无药理活性代谢产物LAY151的血浆浓度。
结果
轻度肝功能损害患者中，维格列汀的暴露量（AUC(0 - ∞)和C(max)）分别非显著降低20%和30%[几何平均比值（90% CI）：AUC(0 - ∞)，0.80（0.60，1.06），p = 0.192；C(max)，0.70（0.46，1.05），p = 0.149]。中度肝功能损害患者中，维格列汀的暴露量也非显著降低[AUC(0 - ∞)降低8%，几何平均比值（90% CI）：0.92（0.69，1.23），p = 0.630；C(max)降低23%，几何平均比值（90% CI）：0.77（0.51，1.17），p = 0.293]。在重度肝功能损害患者中，C(max)比健康受试者低6%[几何平均比值（90% CI）：0.94（0.59，1.49），p = 0.285]，而AUC(0 - ∞)增加22%[几何平均比值（90% CI）：1.22（0.89，1.68），p = 0.816]。与健康受试者相比，在所有肝功能损害组中，LAY151的AUC(0 - ∞)和C(max)分别增加29% - 84%和24% - 63%。肝功能损害患者对单次口服100 mg维格列汀耐受性良好。
结论
轻度、中度或重度肝功能损害患者中维格列汀的暴露量无显著差异；因此，肝功能损害患者无需调整维格列汀剂量。
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