• Nithya Srinivas, Kaitlyn Maffuid, and KashubaAngela D MADMDivision 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. akashuba@unc.edu..
• 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.
• Clin Pharmacokinet. 2018 Sep 1; 57 (9): 1059-1074.

AbstractDespite 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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