基因治疗计算建模的前瞻性方法——病毒基因治疗的焦点。

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-10-01 Epub Date: 2023-10-17 DOI:10.1007/s10928-023-09889-1
Mary P Choules, Peter L Bonate, Nakyo Heo, Jared Weddell
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引用次数: 0

摘要

临床研究发现,基因治疗剂量毒性和剂量疗效数据仍然缺乏,这导致基因治疗剂量选择仍然难以捉摸。模型知情药物开发(MIDD)已成为贯穿药物疗法发现、开发和批准过程的标准工具,并有可能告知剂量-毒性和剂量-疗效关系,以支持基因治疗剂量选择。尽管有这种潜力,基因治疗的MIDD方法仍然不成熟,需要标准化才能用于基因治疗临床项目。为了推进基因治疗的MIDD方法,在这篇综述中,我们首先概述了基因治疗类型,以及它们与生物分析、制剂、给药途径和监管角度的区别。在这种生物学和调控背景下,我们提出了如何利用基于生理学的药代动力学建模和定量系统药理学,在给药后全面了解AAV和靶蛋白动力学,将MIDD用于基于AAV的基因治疗。我们讨论了这一提出的模型,允许对AAV药理学进行深入探索,如何成为该领域治疗这些未满足的疾病人群所需的关键。
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Prospective approaches to gene therapy computational modeling - spotlight on viral gene therapy.

Clinical studies have found there still exists a lack of gene therapy dose-toxicity and dose-efficacy data that causes gene therapy dose selection to remain elusive. Model informed drug development (MIDD) has become a standard tool implemented throughout the discovery, development, and approval of pharmaceutical therapies, and has the potential to inform dose-toxicity and dose-efficacy relationships to support gene therapy dose selection. Despite this potential, MIDD approaches for gene therapy remain immature and require standardization to be useful for gene therapy clinical programs. With the goal to advance MIDD approaches for gene therapy, in this review we first provide an overview of gene therapy types and how they differ from a bioanalytical, formulation, route of administration, and regulatory standpoint. With this biological and regulatory background, we propose how MIDD can be advanced for AAV-based gene therapies by utilizing physiological based pharmacokinetic modeling and quantitative systems pharmacology to holistically inform AAV and target protein dynamics following dosing. We discuss how this proposed model, allowing for in-depth exploration of AAV pharmacology, could be the key the field needs to treat these unmet disease populations.

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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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