Unbound Brain-to-Plasma Partition Coefficient, Kp,uu,brain-a Game Changing Parameter for CNS Drug Discovery and Development

Abstract

Purpose: More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (K_p,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, K_p,uu,brain is the key parameter to obtain unbound brain concentrations from unbound plasma concentrations.

Methods: To understand the importance and impact of the K_p,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 K_p,uu,brain as compared to other parameters related to brain exposure. Adoption of the K_p,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 K_p,uu,brain implementation in their companies as 'game-changing'. Although most companies (74%) consider the current toolbox for K_p,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.

Keywords: CNS drug development; blood–brain barrier; drug transport; neuropharmacokinetics; unbound brain-to-plasma partition coefficient, Kp,uu,brain.