Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: Results from two randomized, double-blind, placebo-controlled studies with single oral doses
Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: Results from two randomized, double-blind, placebo-controlled studies with single oral doses
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DOI：
10.1016/j.clpt.2005.09.002
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发表时间：
2005-12-01
影响因子：
6.7
通讯作者：
Wagner, JA
中科院分区：
文献类型：
--
作者：
Herman, GA;Stevens, C;Wagner, JA
背景：西格列汀([(2R)-4-oxo-4-(3-[trifluoromethyl]-5，6-dihydro[1，2，4]triazolo[4，3-a]-pyrazin-7[8H]-yl)-1-(2，4，5-trifluorophenyl)butan-2-amine])，MK-0431DPP-IV)是一种口服活性、强效和选择性的二肽基肽酶IV抑制剂，目前正处于治疗2型糖尿病的III期开发中。方法：两项双盲、随机、安慰剂对照、交替小组研究评价了该药的安全性、耐受性、药代动力学、结果：西格列汀在健康男性志愿者体内吸收良好(约80%在尿液中排泄不变)，明显的终末半衰期为8~14小时。西格列汀的肾清除量平均为388毫升/分钟，基本不受给药剂量的影响。西格列汀的血药浓度-时间曲线下面积以近似剂量依赖的方式增加，并且不受食物的显著影响。单剂量西格列汀显著且呈剂量依赖性地抑制血浆DPP-IV活性，在12小时内DPP-IV活性在50毫克或以上时抑制约80%或更多，在24小时内在100毫克或更高时抑制约80%或更多。与安慰剂相比，西格列汀产生的餐后活性胰升糖素样肽I水平大约增加了2倍。西格列汀耐受性良好，与低血糖无关。结论：本研究为西格列汀在人体内的药理学特性提供了证据。通过抑制血浆DPP-IV活性，西格列汀增加了正常血糖健康男性志愿者餐后活性高血糖素样多肽1浓度的升高，而不会导致低血糖。西格列汀具有支持每日一次给药方案的药代动力学和药效学特征。
Background: Sitagliptin (MK-0431 [(2R)-4-oxo-4-(3-[trifluoromethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]-pyrazin-7[8H]-yl)-1-(2,4,5-trifluorophenyl)butan-2-amine]) is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-IV) currently in phase III development for the treatment of type 2 diabetes.Methods: Two double-blind, randomized, placebo-controlled, alternating-panel studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of sitagliptin (1.5-600 mg) in healthy male volunteers.Results: Sitagliptin was well absorbed (approximately 80% excreted unchanged in the urine) with an apparent terminal half-life ranging from 8 to 14 hours. Renal clearance of sitagliptin averaged 388 mL/min and was largely uninfluenced by the dose administered. The area under the plasma concentration-time curve for sitagliptin increased in an approximately dose-dependent manner and was not meaningfully influenced by food. Single doses of sitagliptin markedly and dose-dependently inhibited plasma DPP-IV activity, with approximately 80% or greater inhibition of DPP-IV activity occurring at 50 mg or greater over a 12-hour period and at 100 mg or greater over a 24-hour period. Compared with placebo, sitagliptin produced an approximately 2-fold increase in postmeal active glucagon-like peptide I levels. Sitagliptin was well tolerated and was not associated with hypoglycemia.Conclusions: This study provides proof of pharmacologic characteristics for sitagliptin in humans. By inhibiting plasma DPP-IV activity, sitagliptin increases the postprandial rise in active glucagon-like peptide 1 concentrations without causing hypoglycemia in normoglycemic healthy male volunteers. Sitagliptin possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen.