药物动力学/药效学在兽医药物开发和剂量-方案优化中的整合。

AAPS PharmSci Pub Date : 2002-01-01 DOI:10.1208/ps040438
Pierre-Louis Toutain
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引用次数: 0

摘要

药代动力学(PK)/药效学(PD)建模是一种科学工具,可帮助研发人员为确证性临床试验选择合理的剂量方案。本文介绍了传统剂量滴定设计(平行和交叉设计)在确定适当剂量方案方面的一些局限性。文章还解释了 PK/PD 模型如何将 PK 模型(描述剂量、全身药物浓度和时间之间的关系)与 PD 模型(描述全身药物浓度和效应与时间曲线之间的关系)和统计模型(特别是 PK 和/或 PD 起源的个体内和个体间变异性)结合起来。同样重要的是,这些模型有助于根据疗效和选择性促进合理选药。PK/PD 模型的建立可采用多种方法,如直接反应模型与间接反应模型、参数模型与非参数模型。PK/PD 概念可应用于个体剂量优化。本文举例说明了 PK/PD 方法在兽药研发中的应用,并特别强调了非甾体抗炎药物。PK/PD 方法的局限性包括适当模型的开发、替代终点的有效性以及监管环境对这些模型的接受程度。
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Pharmacokinetic/pharmacodynamic integration in drug development and dosage-regimen optimization for veterinary medicine.

Pharmacokinetic (PK)/pharmacodynamic (PD) modeling is a scientific tool to help developers select a rational dosage regimen for confirmatory clinical testing. This article describes some of the limitations associated with traditional dose-titration designs (parallel and crossover designs) for determining an appropriate dosage regimen. It also explains how a PK/PD model integrates the PK model (describing the relationship between dose, systemic drug concentrations, and time) with the PD model (describing the relationship between systemic drug concentration and the effect vs time profile) and a statistical model (particularly, the intra- and interindividual variability of PK and/or PD origin). Of equal importance is the utility of these models for promoting rational drug selection on the basis of effectiveness and selectivity. PK/PD modeling can be executed using various approaches, such as direct versus indirect response models and parametric versus nonparametric models. PK/PD concepts can be applied to individual dose optimization. Examples of the application of PK/PD approaches in veterinary drug development are provided, with particular emphasis given to nonsteroidal anti-inflammatory drugs. The limits of PK/PD approaches include the development of appropriate models, the validity of surrogate endpoints, and the acceptance of these models in a regulatory environment.

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