Towards More Robust Evaluation of the Predictive Performance of Physiologically Based Pharmacokinetic Models: Using Confidence Intervals to Support Use of Model-Informed Dosing in Clinical Care.

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2024-03-01 Epub Date: 2024-02-15 DOI:10.1007/s40262-023-01326-3
Marjolein D van Borselen, Laurens Auke Æmiel Sluijterman, Rick Greupink, Saskia N de Wildt
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引用次数: 0

Abstract

Background and objective: With the rise in the use of physiologically based pharmacokinetic (PBPK) modeling over the past decade, the use of PBPK modeling to underpin drug dosing for off-label use in clinical care has become an attractive option. In order to use PBPK models for high-impact decisions, thorough qualification and validation of the model is essential to gain enough confidence in model performance. Currently, there is no agreed method for model acceptance, while clinicians demand a clear measure of model performance before considering implementing PBPK model-informed dosing. We aim to bridge this gap and propose the use of a confidence interval for the predicted-to-observed geometric mean ratio with predefined boundaries. This approach is similar to currently accepted bioequivalence testing procedures and can aid in improved model credibility and acceptance.

Methods: Two different methods to construct a confidence interval are outlined, depending on whether individual observations or aggregate data are available from the clinical comparator data sets. The two testing procedures are demonstrated for an example evaluation of a midazolam PBPK model. In addition, a simulation study is performed to demonstrate the difference between the twofold criterion and our proposed method.

Results: Using midazolam adult pharmacokinetic data, we demonstrated that creating a confidence interval yields more robust evaluation of the model than a point estimate, such as the commonly used twofold acceptance criterion. Additionally, we showed that the use of individual predictions can reduce the number of required test subjects. Furthermore, an easy-to-implement software tool was developed and is provided to make our proposed method more accessible.

Conclusions: With this method, we aim to provide a tool to further increase confidence in PBPK model performance and facilitate its use for directly informing drug dosing in clinical care.

Abstract Image

对基于生理学的药代动力学模型的预测性能进行更稳健的评估:使用置信区间支持在临床护理中使用模型指导用药。
背景和目的:过去十年来,随着基于生理学的药代动力学(PBPK)建模应用的增加,使用 PBPK 建模来支持临床护理中标签外用药的剂量已成为一种有吸引力的选择。为了利用 PBPK 模型做出具有重大影响的决策,必须对模型进行全面的鉴定和验证,以便对模型的性能有足够的信心。目前,还没有公认的模型验收方法,而临床医生在考虑实施 PBPK 模型指导用药之前,需要对模型的性能有一个明确的衡量标准。我们的目标是缩小这一差距,并建议使用具有预定边界的预测与观察几何平均比的置信区间。这种方法与目前公认的生物等效性测试程序类似,有助于提高模型的可信度和可接受性:方法:概述了构建置信区间的两种不同方法,具体取决于从临床对比数据集中获得的是单个观测数据还是总体数据。以评估咪达唑仑 PBPK 模型为例,演示了这两种测试程序。此外,还进行了一项模拟研究,以证明两倍标准与我们提出的方法之间的差异:利用咪达唑仑成人药代动力学数据,我们证明了建立置信区间比点估计值(如常用的两倍接受标准)能更稳健地评估模型。此外,我们还证明了使用个体预测可以减少所需测试对象的数量。此外,我们还开发并提供了一个易于实施的软件工具,使我们提出的方法更易于使用:通过这种方法,我们旨在提供一种工具,以进一步提高对 PBPK 模型性能的信心,并促进其在临床护理中直接用于指导药物剂量。
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
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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