相关实验视频

Updated: Jun 3, 2025

Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro

Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro

Published on: January 31, 2022

对肝功能障碍 (HI) 试验的新见解

Sebastian Haertter¹, Maximilian Lobmeyer¹, Brian C Ferslew²

¹Clinical Pharmacology, Translational Medicine and Clinical Pharmacology, Boehringer-Ingelheim Pharma, Ingelheim, Germany.

Clinical and translational science

|January 11, 2025

概括

本综述分析了肝功能障碍 (HI) 试验,发现了药物药理动力学 (PK) 的模式,以指导剂量调整. 识别HI中的急剧PK变化可以优化临床试验设计和肝病患者的药物剂量.

科学领域:

药理学药理学是指药理学的学科.
临床药物开发临床药物开发
肝病学肝病学是一种肝病学.

背景情况:

由于药物代谢发生变化,肝功能障碍 (HI) 需要在药物开发中进行剂量调整.
传统的HI试验评估肝病患者的剂量需求.
本综述综合了HI研究的数据,以改进试验设计.

研究的目的:

分析现有的肝功能障碍 (HI) 研究数据.
为了对药物药理动力学 (PK) 的HI影响进行分类.
确定优化HI试验设计和药物剂量的模式.

主要方法:

审查了436个HI研究,提取了273种化合物的PK数据.
根据HI患者和对照组之间的AUC/Cmax比率 (≥2或≤0.5) 将化合物分类为"阳性"或"阴性".
分析了化合物的PK特性,其AUC比率在HI严重程度上急剧增加.

主要成果:

199个化合物是负的,69个是正的 (上升),5个是正的 (下降).
69个阳性化合物中的14个显示AUC比率从轻度到重度HI急剧增加.
急剧增加的化合物通常具有高蛋白结合,高Vd,低生物可用性,较小的脏排泄,并且是CYP3A4/2D6基质,经常是OATP1B1基质.

结论:

在HI中药物PK模式可以告知剂量适应策略.
在HI严重程度上发生急剧PK变化的化合物可能需要进行完整的试验,但允许剂量估计.
具有最小的PK变化的化合物可能允许减少HI试验,可能专注于中度HI.

关键词:

ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME ADME 智商工作组 IQ工作组肝功能受损肝功能受损在文献搜索中搜索文献.药物动力学 (PK) 是指

更多相关视频

Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis

Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis

Published on: March 11, 2017

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment

Published on: December 3, 2020

相关概念视频

Hepatic Drug Clearance: Role of Transporters

Hepatic Drug Clearance: Role of Transporters

In the liver and bile canaliculi, influx and efflux transporters modification can influence intrinsic clearance. Transporters play a significant role in moving drugs within liver cells. Elaborate models, such as the Biopharmaceutical Classification System (BCS), are essential to relate transporters to drug disposition. This system categorizes drugs into four classes based on solubility and permeability, providing insights into elimination routes and the effects of transporters following oral...

Factors Affecting Drug Response: Overview

Factors Affecting Drug Response: Overview

When it comes to infants and young children, they are typically administered smaller doses of medication in comparison to adults. This is primarily because their organ functions still need to fully develop, meaning their bodies are not as efficient at metabolizing or eliminating drugs. Additionally, their blood-brain barrier is more permeable than in adults. As a result, high concentrations of drugs can easily penetrate the central nervous system (CNS), potentially leading to neurological...

Hepatic Drug Clearance: Effect of Protein Binding

Hepatic Drug Clearance: Effect of Protein Binding

Hepatic clearance is influenced by protein binding based on the drug's extraction ratio. Drugs with high extraction ratios are considered flow-limited and remain unaffected by protein binding during hepatic clearance. On the other hand, drugs with low extraction ratios may be impacted by plasma protein binding, although the extent of this influence depends on the fraction of the drug bound.
For low-extraction-ratio drugs that are less than 80% protein-bound, minor changes in protein binding...

Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance

Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance

Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
A recent model describes pravastatin's hepatobiliary excretion,...

Clinical Trials: Overview

Clinical Trials: Overview

Clinical development focuses on how the drug will interact with the human body and encompasses four key phases of clinical trials, each serving a specific purpose in assessing the safety and effectiveness of new drugs. These phases overlap and build upon one another. Phase I involves a small group of healthy volunteers (typically 20-80 individuals) or, in cases where significant toxicity is expected, patients with the targeted disease, such as cancer or AIDS. The volunteers are tested for...

Factors Affecting Renal Clearance: Renal Impairment

Factors Affecting Renal Clearance: Renal Impairment

Renal dysfunction significantly impairs the renal clearance of drugs, leading to potential complications in drug therapy. Renal failure, which can be caused by various factors, poses a significant challenge in the elimination of drugs from the body.
One condition associated with renal failure is uremia. Uremia is characterized by impaired glomerular filtration and fluid accumulation in the body. This condition hinders the renal clearance of drugs, resulting in drug accumulation and potential...