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Clinical Pharmacokinetics and Pharmacodynamics of Drugs in the Central Nervous System

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Abstract

Despite contributing significantly to the burden of global disease, the translation of new treatment strategies for diseases of the central nervous system (CNS) from animals to humans remains challenging, with a high attrition rate in the development of CNS drugs. The failure of clinical trials for CNS therapies can be partially explained by factors related to pharmacokinetics/pharmacodynamics (PK/PD), such as lack of efficacy or improper selection of the initial dosage. A focused assessment is needed for CNS-acting drugs in first-in-human studies to identify the differences in PK/PD from animal models, as well as to choose the appropriate dose. In this review, we summarize the available literature from human studies on the PK and PD in brain tissue, cerebrospinal fluid, and interstitial fluid for drugs used in the treatment of psychosis, Alzheimer’s disease and neuro-HIV, and address critical questions in the field. We also explore newer methods to characterize PK/PD relationships that may lead to more efficient dose selection in CNS drug development.

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Acknowledgements

The authors would like to thank Rachael Posey for devising the search strategy for the review article.

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  1. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, 1094 Genetic Medicine Building, CB# 7361, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA

    Nithya Srinivas, Kaitlyn Maffuid & Angela D. M. Kashuba

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  1. Nithya Srinivas
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  2. Kaitlyn Maffuid
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  3. Angela D. M. Kashuba
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Correspondence to Angela D. M. Kashuba.

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Funding

This work was funded by the Center for AIDS Research (Grant number CFAR P30 AI50410) and the NIH/NIAID (Grant number R01AI111891-04). Nithya Srinivas is supported by the Royster Society of Fellows, UNC Chapel Hill.

Conflicts of interest

Nithya Srinivas, Kaitlyn Maffuid, and Angela Kashuba declare that they have no conflicts of interest that might be relevant to the contents of this article.

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Srinivas, N., Maffuid, K. & Kashuba, A.D.M. Clinical Pharmacokinetics and Pharmacodynamics of Drugs in the Central Nervous System. Clin Pharmacokinet 57, 1059–1074 (2018). https://doi.org/10.1007/s40262-018-0632-y

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