论文标题
多源数据集成的贝叶斯框架 - 临床前研究中的人类外推应用
Bayesian Framework for Multi-Source Data Integration -- Application to Human Extrapolation From Preclinical Studies
论文作者
论文摘要
在临床前研究中,例如在体外和计算机研究中,在前进到第一名试验之前,对药物的药代动力学,药效和毒理学特征进行了评估。通常,对每项研究进行独立分析,并且人剂量范围并不能利用所有研究所获得的知识。考虑到通过推论程序进行临床前数据特别有趣,可以获得更精确,更可靠的起始剂量和剂量范围。我们提出了一个贝叶斯框架,用于推断到人类的临床前研究结果,以预测人类中感兴趣的量(例如最小有效剂量,最大耐受剂量等)。我们建立了一种方法,分为四个主要步骤,基于每项研究的顺序参数估计,外推到人,后验分布之间的可相当性检查和最终信息合并以提高估计的精度。通过广泛的仿真研究评估了新框架,该研究基于Galunisertib的临床前开发启发的肿瘤学示例。与标准框架相比,我们的方法可以更好地使用所有信息,从而减少预测的不确定性,并可能导致更有效的剂量选择。
In preclinical investigations, e.g. in in vitro, in vivo and in silico studies, the pharmacokinetic, pharmacodynamic and toxicological characteristics of a drug are evaluated before advancing to first-in-man trial. Usually, each study is analyzed independently and the human dose range does not leverage the knowledge gained from all studies. Taking into account the preclinical data through inferential procedures can be particularly interesting to obtain a more precise and reliable starting dose and dose range. We propose a Bayesian framework for multi-source data integration from preclinical studies results extrapolated to human, which allow to predict the quantities of interest (e.g. the minimum effective dose, the maximum tolerated dose, etc.) in humans. We build an approach, divided in four main steps, based on a sequential parameter estimation for each study, extrapolation to human, commensurability checking between posterior distributions and final information merging to increase the precision of estimation. The new framework is evaluated via an extensive simulation study, based on a real-life example in oncology inspired from the preclinical development of galunisertib. Our approach allows to better use all the information compared to a standard framework, reducing uncertainty in the predictions and potentially leading to a more efficient dose selection.