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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Impact of target-mediated drug disposition on Linagliptin pharmacokinetics and DPP-4 inhibition in type 2 diabetic patients.
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Impact of target-mediated drug disposition on Linagliptin pharmacokinetics and DPP-4 inhibition in type 2 diabetic patients.

机译：目标介导的药物处置对2型糖尿病患者中利格列汀药代动力学和DPP-4抑制的影响。

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摘要

The pharmacokinetics of the novel dipeptidyl-peptidase 4 (DPP-4) inhibitor linagliptin is nonlinear. Based on in vitro experiments, concentration-dependent binding to DPP-4 is the most likely cause for the nonlinearity. Population pharmacokinetic/pharmacodynamic modeling was performed using linagliptin plasma concentrations and plasma DPP-4 activities from 2 phase 2a studies. In these studies, type 2 diabetic patients received either 1, 2.5, 5, or 10 mg of linagliptin once daily over 12 days (study 1) or 2.5, 5, or 10 mg of linagliptin once daily over 28 days (study 2). The modeling results supported the hypothesis that linagliptin exhibits target-mediated drug disposition. The linagliptin plasma concentrations were best described by a 2-compartment model including concentration-dependent protein binding in the central and peripheral compartment. The plasma DPP-4 activity was included in the model in a semi-mechanistic way by relating it to the model-calculated plasma DPP-4 occupancy with linagliptin. The target binding has a major impact on linagliptin pharmacokinetics. Although unbound linagliptin is cleared efficiently (CL/F 220 L/h), the concentration-dependent binding is responsible for the long terminal half-life (approximatelly 120 hours) of linagliptin and its nonlinear pharmacokinetics. The model allowed a comprehensive understanding of the impact of target-mediated drug disposition and provides a useful tool to support clinical development.
机译：新型二肽基肽酶4（DPP-4）抑制剂利格列汀的药代动力学是非线性的。根据体外实验，DPP-4的浓度依赖性结合是造成非线性的最可能原因。使用利格列汀血浆浓度和来自2a期2a研究的血浆DPP-4活性进行群体药代动力学/药效学建模。在这些研究中，2型糖尿病患者在12天之内每天接受1、2.5、5或10 mg利格列汀（研究1）或在28天之内每天接受2.5、5或10 mg利那列汀（研究2）。建模结果支持了利格列汀表现出靶标介导的药物处置的假设。利格列汀血浆浓度最好由2室模型描述，包括中央和外周室中浓度依赖性蛋白结合。通过将血浆DPP-4活性与模型计算的利拉列汀的血浆DPP-4占有率相关联，以半机械方式将其包括在模型中。靶标结合对利格列汀药代动力学有重大影响。尽管未结合的利格列汀已被有效清除（CL / F 220 L / h），但浓度依赖性的结合导致了利格列汀的长末端半衰期（约120小时）及其非线性药代动力学。该模型可以全面了解靶标介导的药物处置的影响，并提供了支持临床开发的有用工具。

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