通过半机械数学模型解释肿瘤学临床前发展中体外与体内疗效的相关性。

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Heinrich J Huber, Hitesh B Mistry
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引用次数: 0

摘要

体外-体内相关性(IVIVC),将IC50等体外参数与血浆中的体内药物暴露和肿瘤生长联系起来,在肿瘤学中广泛用于实验设计和剂量决策。然而,他们对潜在机制缺乏更深入的了解。因此,我们的论文侧重于将小分子激酶抑制剂的经验IVIVC关系与半机制肿瘤生长模型联系起来。我们开发了一种方法,结合了化合物的峰谷比(PTR)、体外剂量反应曲线的希尔系数和异种移植物特异性等参数。这导致了在线性药代动力学下确定肿瘤停滞有效剂量的公式,与传统的经验IVIVC关系等效,但能够进行更系统的分析。我们的研究结果表明,体内异种移植物特异性参数,特别是生长率(g)和衰变率(d),以及平均暴露量,通常比化合物的峰谷比更重要地决定肿瘤停滞和有效剂量。然而,随着Hill系数的增加,肿瘤停滞对PTR的依赖性变得更加明显,这表明该化合物更受其最大值或低谷值的影响,而不是平均暴露量的影响。此外,我们讨论了我们的方法在临床研究中预测群体剂量范围的转化,并提出了一种仅依赖于特定体内异种移植物参数而非IC50暴露覆盖率的耐药性机制。总之,我们的研究旨在提供对IVIVIVC关系的更深入的机制理解,强调异种移植物特异性参数和PTR对肿瘤停滞的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Explaining in-vitro to in-vivo efficacy correlations in oncology pre-clinical development via a semi-mechanistic mathematical model.

Explaining in-vitro to in-vivo efficacy correlations in oncology pre-clinical development via a semi-mechanistic mathematical model.

In-vitro to in-vivo correlations (IVIVC), relating in-vitro parameters like IC50 to in-vivo drug exposure in plasma and tumour growth, are widely used in oncology for experimental design and dose decisions. However, they lack a deeper understanding of the underlying mechanisms. Our paper therefore focuses on linking empirical IVIVC relations for small-molecule kinase inhibitors with a semi-mechanistic tumour-growth model. We develop an approach incorporating parameters like the compound's peak-trough ratio (PTR), Hill coefficient of in-vitro dose-response curves, and xenograft-specific properties. This leads to formulas for determining efficacious doses for tumor stasis under linear pharmacokinetics equivalent to traditional empirical IVIVC relations, but enabling more systematic analysis. Our findings reveal that in-vivo xenograft-specific parameters, specifically the growth rate (g) and decay rate (d), along with the average exposure, are generally more significant determinants of tumor stasis and effective dose than the compound's peak-trough ratio. However, as the Hill coefficient increases, the dependency of tumor stasis on the PTR becomes more pronounced, indicating that the compound is more influenced by its maximum or trough values rather than the average exposure. Furthermore, we discuss the translation of our method to predict population dose ranges in clinical studies and propose a resistance mechanism that solely relies on specific in-vivo xenograft parameters instead of IC50 exposure coverage. In summary, our study aims to provide a more mechanistic understanding of IVIVC relations, emphasizing the importance of xenograft-specific parameters and PTR on tumor stasis.

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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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