The ability to penetrate the blood-brain barrier (BBB) in order to gain access to the CNS is an essential prerequisite for drug candidates to be able to interfere with drug targets that reside within the brain. Addressing CNS penetration has therefore become an important element in today’s CNS drug discovery. After a brief look at the flawed old concept of maximizing total brain levels, the presentation will focus on the key PK processes that control the unbound brain concentrations as the most relevant exposure parameter for pharmacological CNS activity (1). The presentation discusses strategies, methods and approaches for the optimization of CNS penetration including exemplary lead optimization screening trees of CNS and non-CNS projects. The integration of in vitro and in vivo brain penetration assays and parameters allowing for a rational compound optimization to either maximize or minimize brain penetration is presented (2). In fully acknowledging the ‘free drug hypothesis’ (3) the integrated framework is consistent with the exposure-centered approach to support drug discovery and development by quantitatively linking potency, target exposure, mode-of-action and efficacy by PK/PD modelling (4). References 1 Reichel A. (2014) Integrated Approach to Optimizing CNS Penetration in Drug Discovery: From the Old to the New Paradigm and Assessment of Drug–Transporter Interactions. In: Drug Delivery to the Brain. M. Hammarlund-Udenaes, E. de Lange, R.G. Thorne (Eds.) AAPS Advances in the Pharmaceutical Sciences Series, Springer, New York, p.339-374. 2 Reichel A. (2015) Pharmacokinetics of CNS Penetration. In: Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs. L. Di, E.H. Kerns (Eds.) John Wiley and Sons, New Jersey, p.7-41. 3 Smith DA, Di L, Kerns EH (2010) The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov 9(12):929-939 4 Reichel A. and Lienau P. (2015) Pharmacokinetics in Drug Discovery - An exposure-centered approach to optimizing and predicting drug efficacy and safety. In: New Approaches to Drug Discovery. Handbook of Experimental Pharmacology. in press

Pharmacokinetics and free drug hypothesis for CNS drug candidates

251st National Meeting (2016)

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