John P Prybylski, Yuchen Wang, Vaishali Sahasrabudhe, Vivek Purohit
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引用次数: 0
摘要
在肾功能损害和肝功能损害(RI 和 HI)研究中招募平行的健康参与者(HPs)是评估药代动力学差异的常用策略。这种方法的局限性包括对暴露差异的估计不足,以及在没有益处的人群中使用药物。最近,Purohit 等人(2023 年)发表了一种方法,利用先前基于群体药代动力学(PopPK)建模的模拟来推断 RI/HI 臂和 HPs 之间暴露比的分布。该方法是成功的,但这只是一个单一的例子,其稳健的模型经过了多次反复开发,并与大量的 HP 数据进行了拟合。为了在更多的研究和处于不同开发阶段的模型中进行测试,我们搜索了 RI/HI 研究目录,并使用模拟方法分析了那些具有合适特性且来自具有可用模型的项目的研究。共有 9 项研究被纳入分析。大多数研究都与研究当时(ATT)可用的模型有关,而且所有研究都有一个当前的最终模型。有 3 项研究的 ATT 模型(2 项)或最终模型(1 项)不能很好地预测 HP PK。与传统的方差分析(ANOVA)相比,模拟方法提供了相似的暴露比点估计值和置信区间。在对 HP 数据进行模拟而不是外推,且不存在其他复杂因素的情况下,可以考虑将这种基于 PopPK 的方法作为首选方法。
Simulating Healthy Participant Pharmacokinetics for Renal and Hepatic Impairment Studies: Retrospective Assessment of the Approach.
The recruitment of a parallel, healthy participants (HPs) arm in renal and hepatic impairment (RI and HI) studies is a common strategy to assess differences in pharmacokinetics. Limitations in this approach include the underpowered estimate of exposure differences and the use of the drug in a population for which there is no benefit. Recently, a method was published by Purohit et. al. (2023) that leveraged prior population pharmacokinetic (PopPK) modeling-based simulation to infer the distribution of exposure ratios between the RI/HI arms and HPs. The approach was successful, but it was a single example with a robust model having several iterations of development and fitting to extensive HP data. To test in more studies and models at different stages of development, our catalogue of RI/HI studies was searched, and those with suitable properties and from programs with available models were analyzed with the simulation approach. There were 9 studies included in the analysis. Most studies were associated with models that would have been available at the time (ATT) of the study, and all had a current, final model. For 3 studies, the HP PK was not predicted well by the ATT (2) or final (1) models. In comparison to conventional analysis of variance (ANOVA), the simulation approach provided similar point estimates and confidence intervals of exposure ratios. This PopPK based approach can be considered as a method of choice in situations where the simulation of HP data would not be an extrapolation, and when no other complicating factors are present.
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