Pharmaceutical Research ( IF 3.5 ) Pub Date : 2022-04-11 , DOI: 10.1007/s11095-022-03246-6 Irena Loryan 1 , Andreas Reichel 2 , Bo Feng 3 , Christoffer Bundgaard 4 , Christopher Shaffer 5 , Cory Kalvass 6 , Dallas Bednarczyk 7 , Denise Morrison 8 , Dominique Lesuisse 9 , Edmund Hoppe 10 , Georg C Terstappen 11 , Holger Fischer 12 , Li Di 13 , Nicola Colclough 14 , Scott Summerfield 15 , Stephen T Buckley 16 , Tristan S Maurer 17 , Markus Fridén 1, 18
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Purpose
More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (Kp,uu,brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled by advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support the notion that the unbound (free) concentration of a drug at the site of action, such as the brain, is the driving force for pharmacological responses. Towards this end, Kp,uu,brain is the key parameter to obtain unbound brain concentrations from unbound plasma concentrations.
Methods
To understand the importance and impact of the Kp,uu,brain concept in contemporary drug discovery and development, a survey has been conducted amongst major pharmaceutical companies based in Europe and the USA. Here, we present the results from this survey which consisted of 47 questions addressing: 1) Background information of the companies, 2) Implementation, 3) Application areas, 4) Methodology, 5) Impact and 6) Future perspectives.
Results and conclusions
From the responses, it is clear that the majority of the companies (93%) has established a common understanding across disciplines of the concept and utility of Kp,uu,brain as compared to other parameters related to brain exposure. Adoption of the Kp,uu,brain concept has been mainly driven by individual scientists advocating its application in the various companies rather than by a top-down approach. Remarkably, 79% of all responders describe the portfolio impact of Kp,uu,brain implementation in their companies as ‘game-changing’. Although most companies (74%) consider the current toolbox for Kp,uu,brain assessment and its validation satisfactory for drug discovery and early development, areas of improvement and future research to better understand human brain pharmacokinetics/pharmacodynamics translation have been identified.
中文翻译：
未结合的脑与血浆分配系数，Kp,uu,brain——中枢神经系统药物发现和开发的一个改变游戏规则的参数
目的
自从 Margareta Hammarlund-Udenaes 教授首次描述未结合的脑与血浆分配系数 (K p,uu,brain ) 以来，已经过去了 15 年多的时间，该系数的实现得益于包括脑微透析在内的实验方法的进步。从那时起，越来越多的知识和数据继续支持这样的观点：药物在作用部位（例如大脑）的未结合（游离）浓度是药理反应的驱动力。为此，K p,uu,brain是从未结合血浆浓度获得未结合脑浓度的关键参数。
方法
为了了解 K p,uu,brain概念在当代药物发现和开发中的重要性和影响，我们对欧洲和美国的主要制药公司进行了一项调查。在这里，我们展示了这项调查的结果，其中包括 47 个问题，涉及：1) 公司的背景信息、2) 实施、3) 应用领域、4) 方法、5) 影响和 6) 未来前景。
结果和结论
从答复中可以明显看出，与与大脑暴露相关的其他参数相比，大多数公司 (93%) 对 K p,uu,brain的概念和效用建立了跨学科的共识。K p,uu,brain概念的采用主要是由个别科学家推动的，他们提倡将其应用于各个公司，而不是通过自上而下的方法。值得注意的是，79% 的受访者将其公司实施K p,uu,brain 的投资组合影响描述为“改变游戏规则”。尽管大多数公司 (74%) 认为当前的 K p,uu,brain评估工具箱及其验证对于药物发现和早期开发来说令人满意，但已经确定了改进领域和未来研究，以更好地理解人脑药代动力学/药效学转化。
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