论文标题

I期剂量降低试验的贝叶斯贝叶斯时间药代动力学模型

A Bayesian time-to-event pharmacokinetic model for phase I dose-escalation trials with multiple schedules

论文作者

Günhan, Burak Kürsad, Weber, Sebastian, Friede, Tim

论文摘要

第一阶段剂量提升试验必须以安全模型为指导,以避免使患者面临不可接受的高毒性风险。传统上,这些试验基于一种日程安排。但是,在最近的实践中,通常需要考虑多个时间表,这意味着除了剂量本身之外,在试验中还需要改变时间表。因此,目的是找到一种可接受的剂量 - 安排组合。但是,大多数已建立的剂量降低试验方法旨在升级剂量,并且必须做出临时选择,以使其适应更复杂的设置,以找到可接受的剂量固定组合。在本文中,我们引入了贝叶斯到事实的模型,该模型通过使用药代动力学原理明确考虑了剂量量和时间表。该模型使用时间变化的暴露措施来说明随着时间的推移剂量限制毒性的风险。剂量划分的决策通过过量控制标准的升级来告知。该模型是使用可解释的参数制定的,该参数有助于先验的规范。在一项仿真研究中,我们将提出的方法与现有方法进行了比较。仿真研究表明,与现有方法相比,在建议可接受的剂量 - 安排组合方面,所提出的方法与现有方法相比产生相似或更好的结果,但减少了大多数情况下招募的患者数量。 \ texttt {r}和\ texttt {stan}代码实现所提出的方法可从github(\ url {https://github.com/gunhanb/titepk_code})公开获得。

Phase I dose-escalation trials must be guided by a safety model in order to avoid exposing patients to unacceptably high risk of toxicities. Traditionally, these trials are based on one type of schedule. In more recent practice, however, there is often a need to consider more than one schedule, which means that in addition to the dose itself, the schedule needs to be varied in the trial. Hence, the aim is finding an acceptable dose-schedule combination. However, most established methods for dose-escalation trials are designed to escalate the dose only and ad-hoc choices must be made to adapt these to the more complicated setting of finding an acceptable dose-schedule combination. In this paper, we introduce a Bayesian time-to-event model which takes explicitly the dose amount and schedule into account through the use of pharmacokinetic principles. The model uses a time-varying exposure measure to account for the risk of a dose-limiting toxicity over time. The dose-schedule decisions are informed by an escalation with overdose control criterion. The model is formulated using interpretable parameters which facilitates the specification of priors. In a simulation study, we compared the proposed method with an existing method. The simulation study demonstrates that the proposed method yields similar or better results compared to an existing method in terms of recommending acceptable dose-schedule combinations, yet reduces the number of patients enrolled in most of scenarios. The \texttt{R} and \texttt{Stan} code to implement the proposed method is publicly available from Github (\url{https://github.com/gunhanb/TITEPK_code}).

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