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

• DOI: 10.1007/s11095-022-03246-6
• Publication Date: 2022-04-11T21:02:40Z
• Authors: Irena Loryan; Andreas Reichel; Bo Feng; Christoffer Bundg...; Christopher Shaffer; Cory Kalvass; Dallas Bednarczyk; Denise Morrison; Dominique Lesuisse; Edmund Hoppe; Georg C. Terstappen; Holger Fischer; Li Di; Nicola Colclough; Scott Summerfield; Stephen T. Buckley; Tristan S. Maurer; Markus Fridén
• Keywords: Toolbox; Drug Development

More than 15 years have passed since the first description of unbound brain-to-plasma partition coefficient (Kp,uu,brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support notion that (free) concentration a drug at site action, such as brain, is driving force for pharmacological responses. Towards this end, Kp,uu,brain key parameter obtain brain concentrations from plasma concentrations.To understand importance impact concept contemporary discovery development, survey has been conducted amongst major pharmaceutical companies based Europe USA. Here, we present results consisted 47 questions addressing: 1) Background information companies, 2) Implementation, 3) Application areas, 4) Methodology, 5) Impact 6) Future perspectives.From responses, it clear majority (93%) established common understanding across disciplines utility compared other parameters related exposure. Adoption mainly driven individual scientists advocating its application various rather top-down approach. Remarkably, 79% all responders describe portfolio implementation their 'game-changing'. Although most (74%) consider current toolbox assessment validation satisfactory early areas improvement future research better human pharmacokinetics/pharmacodynamics translation identified.