Intra-Target Microdosing (ITM): A Novel Drug Development Approach Aimed at Enabling Safer and Earlier Translation of Biological Insights Into Human Testing.
Intra-Target Microdosing (ITM): A Novel Drug Development Approach Aimed at Enabling Safer and Earlier Translation of Biological Insights Into Human Testing.
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DOI：
10.1111/cts.12464
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Lappin G
中科院分区：
文献类型：
--
作者：
Burt T;Noveck RJ;MacLeod DB;Layton AT;Rowland M;Lappin G
靶内微量给药（ITM）是一个新概念，它融合了两种不同的技术：“微量给药”和靶内（例如，动脉内，肌肉内，鞘内，局部，皮下）药物递送，其中正在开发的药物在其首次人体（FIH）研究中局部给药，仅在总体重的一小部分（约1/100）中产生治疗水平的暴露。当药物进入体循环时，它被稀释（约100倍），使得产生的全身浓度是亚药理学的，符合微剂量的定义，具有隐含的安全性特征和相关的监管宽松。靶器官最初暴露于药理学浓度，尽管时间很短，但可能足以产生指示药物局部疗效和/或毒性的生物标志物反应。这种局部药效学（PD）数据可以通过靶点的成像或其他生理测试在引流靶点的静脉中收集，这可能与其他器官/组织中的全身效应和作用相关。人体组织在体内暴露于供试品的药理学知识是临床前药物实验的关键“缺失环节”，对于开发决策非常宝贵。在最近的一篇出版物中，我们提出了术语“人体”来描述这种类型的测试，在活体中进行，没有治疗目的，全身暴露和相关毒性风险最小。因此，ITM提供了一种新的药物开发方法，通过允许更安全，更早，更快和相对便宜的新药安全性，有效性和药代动力学（PK）测试来补充和增强现有的药物开发“工具包”。在这篇概念文章中，我们涵盖了监管背景、理论和概念方面，讨论了概念验证和可行性研究以及用于将数据外推至完整的药理学水平暴露的相关数学建模，概述了一些应用，最后讨论了该方法的局限性。
BACKGROUNDIntra‐target microdosing (ITM) is a novel concept that amalgamates two disparate techniques:“microdosing” and intra‐target (eg, intra‐arterial, intra‐muscular, intra‐thecal, topical, subcutaneous) drug delivery whereby a drug under development is administered in its first‐in‐human (FIH) study locally leading to therapeutic‐level exposure only in a small proportion (about 1/100 th) of the total body mass. When the drug enters the systemic circulation it is diluted (about 100‐fold) such that the resulting systemic concentration is subpharmacological, meeting the definition of a microdose, with the implied safety profile and associated regulatory leniency. The initial exposure of the target organ to pharmacological concentrations, albeit for a short period of time, may be sufficient to generate responses of biomarkers indicative of the drug's local efficacy and/or toxicity. Such local pharmacodynamic (PD) data could be collected either in the vein draining the target, through imaging or other physiological testing of the target, which could be relevant to systemic effects and actions in other organs/tissues. Such knowledge on pharmacological exposure of human tissue in vivo to test articles is the critical “missing link” of preclinical drug experimentation and would be invaluable for developmental decision making. In a recent publication we proposed the term “in‐humano” to describe this type of testing, conducted in the living human with no therapeutic intent, with minimal systemic exposure and associated toxicity risks. 1 ITM thus offers to be a novel drug development approach, complementing and augmenting the existing drug development “tool‐kit” by allowing the safer, earlier, quicker, and relatively inexpensive safety, efficacy, and pharmacokinetic (PK) testing of new drugs in targeted human organs or tissues of interest. In this concept article we cover the regulatory background, theoretical and conceptual aspects, discuss the proof of concept and feasibility studies and related mathematical modeling used to extrapolate the data to the full, pharmacological‐level exposure, outline some of the applications, and finally discuss the limitations of the approach.
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影响因子：
9.3
作者：
Burt, Tal;Rouse, Douglas C.;Noveck, Robert J.
通讯作者：
Noveck, Robert J.
影响因子：
9.3
作者：
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影响因子：
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作者：
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影响因子：
12.3
作者：
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通讯作者：
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影响因子：
3.5
作者：
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通讯作者：
Beneke, Manfred