Chapter 10 - Blood-Brain Barrier

Abstract

Brain exposure is of interest to all therapeutic areas. Central nervous system (CNS) drug discovery works to optimize brain exposure to improve efficacy. Peripheral drug discovery attempts to minimize brain exposure to eliminate side effects. The central focus is unbound brain concentration (Cb,u), because it is correlated to efficacy. Cb,u is reduced by low blood-brain barrier (BBB) permeation and efflux. The BBB comprises the endothelial cell layer of the brain microcapillary blood vessels. It has multiple characteristics that limit permeation of drugs from blood to brain cells: (a) efflux transporters, (b) restricted passive diffusion, (c) absence of fenestrations, and (d) absence of paracellular permeation. ADME (absorption, distribution, metabolism, and excretion) processes that affect unbound drug concentration in plasma (Cp,u) also limit Cb,u, including low absorption, low metabolic stability, and biliary elimination. As a result, compounds that could otherwise produce therapeutic CNS effects cannot reach CNS targets at sufficient unbound concentrations. Cb,u of a new CNS drug candidate is optimized by improving BBB permeation, reducing efflux transport and the ADME processes that enhance Cp,u. Current strategies for CNS drug exposure now focus on Cb,u, AUCb,u, unbound brain-blood distribution (Kp,uu), efflux ratio, and BBB permeability (Papp). Cb,u is optimized by increasing BBB passive transcellular diffusion permeation, reducing BBB efflux, increasing absorption (solubility, permeability), and reducing clearance (metabolic stability, heparobiliary clearance).