研究暴露-反应关系的纵向药代动力学和时间-事件数据联合模型:阿来替尼的概念验证研究。

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-09-01 Epub Date: 2024-07-11 DOI:10.1007/s00280-024-04698-w
Lishi Lin, Vincent van der Noort, Neeltje Steeghs, Gerrina Ruiter, Jos H Beijnen, Alwin D R Huitema
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引用次数: 0

摘要

目的:在口服靶向抗癌药物的暴露-反应分析中,纵向血浆谷浓度通常被汇总为一个单一值,即使血浆谷浓度会因剂量适应性等因素而随时间变化。本研究的目的是将联合模型与传统的暴露-反应分析方法进行比较,并应用阿来替尼作为概念验证:联合模型结合了纵向药代动力学数据和无进展生存期数据,以推断两种数据类型之间的依赖性和关联性。比较了最佳联合模型和标准与时间相关的 cox 比例危险度模型的结果。为了对数据进行归一化处理,阿来替尼的谷值浓度在进入模型前使用西格玛转换法归一化为转化谷值浓度(TTC):结果:在不同的Cox模型中均未观察到具有统计学意义的暴露-反应关系。相反,将 TTC 的当前值与一段时间内的平均 TTC 相结合的联合模型确实显示出阿来替尼的暴露-反应关系。平均TTC每增加一个单位,病情进展率就会降低11%(HR,0.891;95%置信区间,0.805-0.988):联合模型能够揭示血浆谷浓度与生存结果之间的关联结构,而使用 Cox 模型则无法做到这一点。因此,在口服靶向抗癌药的暴露-反应分析中应更多地使用联合模型。
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A joint model of longitudinal pharmacokinetic and time-to-event data to study exposure-response relationships: a proof-of-concept study with alectinib.

Purpose: In exposure-response analyses of oral targeted anticancer agents, longitudinal plasma trough concentrations are often aggregated into a single value even though plasma trough concentrations can vary over time due to dose adaptations, for example. The aim of this study was to compare joint models to conventional exposure-response analyses methods with the application of alectinib as proof-of-concept.

Methods: Joint models combine longitudinal pharmacokinetic data and progression-free survival data to infer the dependency and association between the two datatypes. The results from the best joint model and the standard and time-dependent cox proportional hazards models were compared. To normalize the data, alectinib trough concentrations were normalized using a sigmoidal transformation to transformed trough concentrations (TTC) before entering the models.

Results: No statistically significant exposure-response relationship was observed in the different Cox models. In contrast, the joint model with the current value of TTC in combination with the average TTC over time did show an exposure-response relationship for alectinib. A one unit increase in the average TTC corresponded to an 11% reduction in progression (HR, 0.891; 95% confidence interval, 0.805-0.988).

Conclusion: Joint models are able to give insights in the association structure between plasma trough concentrations and survival outcomes that would otherwise not be possible using Cox models. Therefore, joint models should be used more often in exposure-response analyses of oral targeted anticancer agents.

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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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