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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Dichloroacetate: population pharmacokinetics with a pharmacodynamic sequential link model.
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Dichloroacetate: population pharmacokinetics with a pharmacodynamic sequential link model.

机译：二氯乙酸盐：具有药效学顺序链接模型的群体药代动力学。

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摘要

Dichloroacetate (DCA) is a small molecule that reduces ambient concentrations of lactate in man. It was the purpose of this study to develop pharmacokinetic and pharmacodynamic models for determination of a dose for a pivotal Phase III clinical trial of DCA in patients with traumatic brain injury (TBI). Population pharmacokinetic and pharmacodynamic models were developed for DCA using NONMEM software. The pharmacokinetic data were fit to a physiologic two-compartment model, and the pharmacodynamic data were fit to an indirect physiologic response model. Simulations were employed to evaluate various dosing strategies for consideration in a pivotal Phase III clinical trial of DCA. For the pharmacokinetic model, it was discovered that the clearance of DCA decreased on multiple dosing from 4.82 L/h to 1.07 L/h and that the pharmacokinetics and pharmacodynamics in TBI patients could not be predicted from normal volunteers. Population pharmacokinetic modeling and simulation of the expected effects of several dosing strategies were useful procedures for designing a Phase III trial.
机译：二氯乙酸盐（DCA）是一种小分子，可降低人体内乳酸的环境浓度。这项研究的目的是开发药代动力学和药效学模型，用于确定创伤性脑损伤（TBI）患者DCA的关键III期临床试验剂量。使用NONMEM软件为DCA开发了群体药代动力学和药效学模型。药代动力学数据适合于生理两室模型，药效动力学数据适合于间接生理反应模型。模拟被用来评估各种剂量策略，以在DCA的关键性III期临床试验中予以考虑。对于药代动力学模型，发现多次给药后DCA的清除率从4.82 L / h降低至1.07 L / h，并且正常志愿者无法预测TBI患者的药代动力学和药效学。人群药代动力学建模和几种给药策略预期效果的模拟是设计III期临床试验的有用程序。

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