药代动力学、药效学和耐受性的概要文件dipeptidyl peptidase-4抑制剂alogliptin:一项随机、双盲、安慰剂对照、multiple-dose研究成人2型糖尿病患者。

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卡温顿P, Christopher R,达文波特M,斑点P, Mekki QA,呃,什么时候卡里姆

药代动力学、药效学和耐受性的概要文件dipeptidyl peptidase-4抑制剂alogliptin:一项随机、双盲、安慰剂对照、multiple-dose研究成人2型糖尿病患者。

其他。2008年3月,30 (3):499 - 512。doi: 10.1016 / j.clinthera.2008.03.004。

PubMed ID

18405788 (在PubMed

]

文摘

背景:Alogliptin是一种高度选择性dipeptidyl peptidase-4 (DPP-4)抑制剂,是正在开发的治疗2型糖尿病(T2D)。目的:本研究是评价药代动力学(PK),进行药效学(PD),耐受性的概要文件和探索多种口服剂量的疗效alogliptin T2D患者。方法:随机、双盲、安慰剂对照,与这些相应平行的组织研究中,患者T2D年龄在18到75年被分配到接受单剂量口服alogliptin 25日100,或400毫克或安慰剂(4:4:4:3比率)每天一次14天。PK概要文件和等离子体在天1和14日DPP-4抑制进行了评估。耐受性是基于监测不良事件(AEs)和临床评估。疗效终点包括4餐后血浆葡萄糖(PPG)和胰岛素浓度,和禁食糖化血红蛋白(HbA (1 c))、c -肽、果糖胺值。结果:56个登记患者(57%女性;93%的白人;平均年龄55.6岁;平均体重89.8公斤; mean body mass index, 31.7 kg/m(2)), 54 completed the study. On day 14, the median T(max) was ~1 hour and the mean t(1/2) was 12.5 to 21.1 hours across all alogliptin doses. Alogliptin was primarily excreted renally (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60.8%-63.4%). On day 14, mean peak DPP-4 inhibition ranged from 94% to 99%, and mean inhibition at 24 hours after dosing ranged from 82% to 97% across all alogliptin doses. Significant decreases from baseline to day 14 were observed in mean 4-hour PPG after breakfast with alogliptin 25 mg (-32.5 mg/dL; P=0.008), 100 mg (-37.2; P=0.002), and 400 mg (-65.6 mg/dL; P<0.001) compared with placebo (+8.2 mg/dL). Significant decreases in mean 4-hour PPG were also observed for alogliptin 25, 100, and 400 mg compared with placebo after lunch (-15.8 mg/dL [P=0.030]; -29.2 mg/dL [P=0.002]; -27.1 mg/dL [P=0.009]; and +14.3 mg/dL, respectively) and after dinner (-21.9 mg/dL [P=0.017]; -39.7 mg/dL [P<0.001]; -35.3 mg/dL [P=0.003]; and +12.8 mg/dL). Significant decreases in mean HbA(1c) from baseline to day 15 were observed for alogliptin 25 mg (-0.22%; P=0.044), 100 mg (-0.40%; P<0.001), and 400 mg (-0.28%; P=0.018) compared with placebo (+0.05%). Significant decreases in mean fructosamine concentrations from baseline to day 15 were observed for alogliptin 100 mg (-25.6 micromol/L; P=0.001) and 400 mg (-19.9 micromol/L; P=0.010) compared with placebo (+15.0 micromol/L). No statistically significant changes were noted in mean 4-hour postprandial insulin or mean fasting C-peptide. No serious AEs were reported, and no patients discontinued the study because of an AE. The most commonly reported AEs for alogliptin 400 mg were headache in 6 of 16 patients (compared with 0/15 for alogliptin 25 mg, 1/14 for alogliptin 100 mg, and 3/11 for placebo), dizziness in 4 of 16 patients (compared with 1/15, 2/14, and 1/11, respectively), and constipation in 3 of 16 patients (compared with no patients in any other group). No other individual AE was reported by >2 patients receiving the 400-mg dose. Apart from dizziness, no individual AE was reported by >1 patient receiving either the 25- or 100-mg dose. CONCLUSIONS: In these adult patients with T2D, alogliptin inhibited plasma DPP-4 activity and significantly decreased PPG levels. The PK and PD profiles of multiple doses of alogliptin in this study supported use of a once-daily dosing regimen. Alogliptin was generally well tolerated, with no dose-limiting toxicity.

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药物

Alogliptin