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Integrated Approach to Optimizing CNS Penetration in Drug Discovery: From the Old to the New Paradigm and Assessment of Drug–Transporter Interactions

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Drug Delivery to the Brain

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 10))

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.

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Authors and Affiliations

  1. Research Pharmacokinetics, DMPK, Global Drug Discovery, Bayer Pharma AG, Müllerstrasse 178, Berlin, 13353, Germany

    Andreas Reichel

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  1. Andreas Reichel
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Correspondence to Andreas Reichel .

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Editors and Affiliations

  1. Pharmaceutical Biosciences, Uppsala University Pharmacokinetics and Drug Therapy, Uppsala, Sweden

    Margareta Hammarlund-Udenaes

  2. LACDR/Pharmacology, Leiden University, Leiden, The Netherlands

    Elizabeth C.M. de Lange

  3. Pharmaceutical Sciences Division, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA

    Robert G. Thorne

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© 2014 American Association of Pharmaceutical Scientists

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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: Hammarlund-Udenaes, M., de Lange, E., Thorne, R. (eds) Drug Delivery to the Brain. AAPS Advances in the Pharmaceutical Sciences Series, vol 10. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9105-7_12

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