Integrated approach to optimizing CNS penetration in drug discovery: From the old to the new paradigm and assessment of drug-transporter interactions

Abstract

Assessing CNS penetration in drug discovery and development is important for both CNS projects and non-CNS projects that aim to improve desired or to avoid unwanted central effects of their drug candidates. After a brief reasoning on the flawed old concept of maximising total brain levels, the chapter describes the key principles of the new paradigm of examining CNS penetration and distribution by integrating those parameters and processes that are crucial in controlling unbound brain concentrations as surrogate for the pharmacologically active drug concentration in brain. As a consequence, Kp,uu,brain is about to replace the total brain/plasma ratio Kp,brain as measure of the extent of brain penetration. The chapter outlines strategies, methods and approaches both for the optimisation of CNS penetration as well as for avoiding it, including exemplary lead optimisation screening trees of CNS and non-CNS projects. A comprehensive framework is given linking the pharmacokinetics of a compound in the body’s periphery to its central (unbound) exposure and subsequent PKPD relation in animal models of efficacy, including considerations for the translation of the PKPD relationships from rodents to larger animals and human. The chapter furthermore summarises current knowledge of drug-transporter interactions at the level of the BBB, and outlines the potential of the new concept for refueling the fading interest in CNS drug discovery and development as a result of too many clinical trial failures and an insufficient understanding of the reasons.