Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics |
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Authors: | Elizabeth C. M. de Lange Willem van den Brink Yumi Yamamoto Wilhelmus E. A. de Witte Yin Cheong Wong |
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Affiliation: | 1. Leiden Academic Center of Drug Research, Translational Pharmacology, Leiden University, Leiden, The Netherlandsecmdelange@lacdr.leidenuniv.nl;3. Leiden Academic Center of Drug Research, Translational Pharmacology, Leiden University, Leiden, The Netherlands |
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Abstract: | Introduction: CNS drug development has been hampered by inadequate consideration of CNS pharmacokinetic (PK), pharmacodynamics (PD) and disease complexity (reductionist approach). Improvement is required via integrative model-based approaches.Areas covered: The authors summarize factors that have played a role in the high attrition rate of CNS compounds. Recent advances in CNS research and drug discovery are presented, especially with regard to assessment of relevant neuro-PK parameters. Suggestions for further improvements are also discussed.Expert opinion: Understanding time- and condition dependent interrelationships between neuro-PK and neuro-PD processes is key to predictions in different conditions. As a first screen, it is suggested to use in silico/in vitro derived molecular properties of candidate compounds and predict concentration-time profiles of compounds in multiple compartments of the human CNS, using time-course based physiology-based (PB) PK models. Then, for selected compounds, one can include in vitro drug-target binding kinetics to predict target occupancy (TO)-time profiles in humans. This will improve neuro-PD prediction. Furthermore, a pharmaco-omics approach is suggested, providing multilevel and paralleled data on systems processes from individuals in a systems-wide manner. Thus, clinical trials will be better informed, using fewer animals, while also, needing fewer individuals and samples per individual for proof of concept in humans. |
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Keywords: | Attrition mastermind research approach physiologically-based pharmacokinetic model target occupancy systems pharmacology pharmacometabolomics |
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