Incorporation of healthy volunteers data on receptor occupancy into a phase II proof-of-concept trial using a Bayesian dynamic borrowing design

IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY
Fulvio Di Stefano, Christelle Rodrigues, Stephanie Galtier, Sandrine Guilleminot, Veronique Robert, Mauro Gasparini, Gaelle Saint-Hilary
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Abstract

Receptor occupancy in targeted tissues measures the proportion of receptors occupied by a drug at equilibrium and is sometimes used as a surrogate of drug efficacy to inform dose selection in clinical trials. We propose to incorporate data on receptor occupancy from a phase I study in healthy volunteers into a phase II proof-of-concept study in patients, with the objective of using all the available evidence to make informed decisions. A minimal physiologically based pharmacokinetic modeling is used to model receptor occupancy in healthy volunteers and to predict it in the patients of a phase II proof-of-concept study, taking into account the variability of the population parameters and the specific differences arising from the pathological condition compared to healthy volunteers. Then, given an estimated relationship between receptor occupancy and the clinical endpoint, an informative prior distribution is derived for the clinical endpoint in both the treatment and control arms of the phase II study. These distributions are incorporated into a Bayesian dynamic borrowing design to supplement concurrent phase II trial data. A simulation study in immuno-inflammation demonstrates that the proposed design increases the power of the study while maintaining a type I error at acceptable levels for realistic values of the clinical endpoint.

使用贝叶斯动态借用设计将健康志愿者的受体占用数据纳入II期概念验证试验。
靶组织中的受体占有率测量药物在平衡状态下所占受体的比例,有时用作药物疗效的替代品,以告知临床试验中的剂量选择。我们建议将健康志愿者第一阶段研究的受体占用数据纳入患者第二阶段概念验证研究,目的是利用所有可用证据做出明智的决定。基于最小生理学的药代动力学建模用于对健康志愿者的受体占用进行建模,并在II期概念验证研究的患者中预测受体占用,同时考虑到群体参数的可变性以及与健康志愿者相比由病理状况引起的特异性差异。然后,给定受体占有率和临床终点之间的估计关系,得出II期研究的治疗组和对照组中临床终点的信息先验分布。这些分布被纳入贝叶斯动态借用设计中,以补充并发的II期试验数据。免疫炎症的模拟研究表明,所提出的设计增加了研究的能力,同时将I型误差保持在临床终点的实际值可接受的水平。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biometrical Journal
Biometrical Journal 生物-数学与计算生物学
CiteScore
3.20
自引率
5.90%
发文量
119
审稿时长
6-12 weeks
期刊介绍: Biometrical Journal publishes papers on statistical methods and their applications in life sciences including medicine, environmental sciences and agriculture. Methodological developments should be motivated by an interesting and relevant problem from these areas. Ideally the manuscript should include a description of the problem and a section detailing the application of the new methodology to the problem. Case studies, review articles and letters to the editors are also welcome. Papers containing only extensive mathematical theory are not suitable for publication in Biometrical Journal.
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