药动学和药效学性质多种口服一定剂量的sitagliptin、一个dipeptidyl peptidase-IV抑制剂:一项双盲,随机,安慰剂对照研究在健康男性志愿者。

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伯格曼AJ,史蒂文斯C,周Y, B, Laethem M,迪斯美特M,斯奈德K, Hilliard D,田中W,曾庆红W, Tanen M,王AQ,陈L,温菲尔G,戴维斯MJ, Ramael年代,瓦格纳是的,赫尔曼GA

药动学和药效学性质多种口服一定剂量的sitagliptin、一个dipeptidyl peptidase-IV抑制剂:一项双盲,随机,安慰剂对照研究在健康男性志愿者。

其他。2006年1月,28 (1):55 - 72。

PubMed ID

16490580 (在PubMed

]

文摘

背景:Dipeptidyl peptidase-IV (DPP-IV)抑制剂代表一个新类口服降糖药代理。Sitagliptin是一种口服活性和选择性DPP-IV抑制剂目前三期治疗2型糖尿病的发展。摘要目的:本研究的目的是评估的药代动力学和药效学(PK / PD)属性和耐受性sitagliptin多个口服每日一次或每天剂量。方法:双盲,随机,安慰剂对照,增量剂口服研究在SGS生物制药,安特卫普,比利时。健康,不吸烟的男性志愿者年龄在18岁到45岁的肌酐清除率> 80毫升/分钟和normoglycemia重15%的理想身高/体重范围内被随机分配到1 8治疗组:sitagliptin 25、50、100、200、或400毫克或安慰剂,QD 10天;sitagliptin的单剂量800毫克注射1天600 mg QD 3 - 10天;或sitagliptin 300毫克竞购10天。PK属性的分析,获得的血浆和尿液样本之前研究药品监督管理局1和0.5天,1,2,4,6,8,10,12日和16小时后研究药物管理局1天;在研究药物管理局天2到9;每24小时和96小时后最后剂量10天,sitagliptin浓度和分析。 Assays were used to measure inhibition of plasma DPP-IV activity and plasma concentrations of active and total glucagon-like peptide-1 (GLP-1), glucose, and glucagon, and serum concentrations of insulin, C-peptide, insulin-like growth factor-1, and insulin like growth factor binding protein-3. Tolerability was assessed throughout the study using physical examination, including vital sign measurements; 12-lead electrocardiography; and laboratory analysis, including hematology, biochemistry (hepatic aminotransferase and creatine phosphokinase), and urinalysis. RESULTS: Seventy subjects were enrolled (mean age, 32.9 years [range, 18-45 years]; mean weight, 79.7 kg [range, 63.4-97.7 kg]; 8 patients per sitagliptin study group and 14 patients in the control group). In the sitagliptin groups, the plasma concentration-time profiles and principal PK parameters (T(max), C(max), and t((1/2))) were statistically similar at days 1 (single dose) and 10 (steady state). In the groups receiving sitagliptin QD doses, accumulation of sitagliptin was modest (AUC accumulation ratio [day 10/day 1] range, 1.05-1.29), and the apparent terminal elimination t((1/2)) was 11.8 to 14.4 hours. At steady state in the sitagliptin QD groups, the mean proportion of drug excreted unchanged in the urine was approximately 70.6%. Dose-dependent inhibition of plasma DPP-IV activity was apparent, and the pattern of inhibition at steady state (day 10) was statistically similar to that observed on day 1. Day-10 weighted mean inhibition of plasma DPP-IV activity over 24 hours was > or = 80% for doses of > or = 50 mg QD. After a standard meal, active GLP-1 concentrations were significantly increased in the sitagliptin groups by approximately 2-fold compared with that in the control group, a finding consistent with near-maximal acute glucose lowering in preclinical studies. Across doses, no apparent adverse effects, including hypoglycemia, were found or reported. CONCLUSIONS: The results from this study in a select population of healthy male volunteers suggest that multiple oral doses of sitagliptin inhibited plasma DPP-IV activity and affected active GLP-1 concentrations in a dose-dependent manner, without producing hypoglycemia. Multiple dosing of sitagliptin exhibited a PK/PD profile consistent with that of a QD regimen and was well tolerated.

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药物靶点

药物	目标	类	生物	药理作用	行动
Sitagliptin	Dipeptidyl肽酶4	蛋白质	人类	是的	抑制剂	细节