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 (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.

A Historical Review of Brain Drug Delivery

“…Instead, industry seeks a unified parameter of drug distribution into brain, such as the CSF concentration, for biologics, or the log BB for small molecules. The 'BB' parameter, which is the ratio of total drug in brain divided by the total drug in blood (or plasma), has given way to the K p,uu [1200], which is the ratio of free drug in brain divided by the free drug in blood (or plasma), as defined in Equation (3). Underlying the use of the K p,uu is the likely supposition that the concentration of drug in brain that drives receptor occupancy is the free drug in brain, not the tissuebound drug in brain.…”

“…The problem with the interpretation of data on the K p,uu parameter relates to how the 'free drug in plasma', and the 'free drug in brain', are experimentally determined. The 'free drug' methods advocated by industry allow for the measurement of the free drug in plasma and brain with in vitro methods, such as equilibrium dialysis of an aliquot of plasma in parallel with an aliquot of brain homogenate [1200].…”

Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo

“…The plasma concentration plummeted to the baseline within 2 h. Measurement of brain and plasma AUC over time, offered a brain and plasma ratio (B/P ratio) of 2.334, indicating that sulfanegen satisfactorily permeates into the brain to a therapeutically relevant extent. The relatively short plasma half-life of sulfanegen prevented estimation of free, protein unbound concentration of sulfanegen and calculation of the unbound partition coefficient (Kp, uu) [ 61 ], a true measure of the brain exposure of a compound.…”

Multiphysics Simulation in Drug Development and Delivery

“…The combination with pharmacodynamics (PD) models further enable describing the response of the studied system to drugs. Given these advantages, PK/PD models have been seen significant adoption to optimise dose and regimen [13], develop effective drugs [14], scale laboratory experiments to clinical trials [15], and explore and examine the physiological barriers in drug delivery [16], particularly the delivery to the central nervous system [17,18]. Unlike PK/PD models, transport-based models are able to accommodate the realistic geometry of the entire tissue or tissue microstructure for outputting both the temporal drug concentration and spatial distribution.…”