Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics. (3rd June 2018)

• Record Type: Journal Article
• Authors: van den Brink, W. J.; Hankemeier, T.; van der Graaf, P. H.; de Lange, E. C. M.
• Is Part Of: Expert opinion on drug discovery. Volume 13:Number 6(2018:Jun.)
• Page Start: 539
• Page End: 550
• Publication Date: 2018-06-03
• Subjects: Biomarkers -- CNS drug development -- interspecies scaling -- pharmacometabolomics -- PK/PD modeling -- systems pharmacology; 615.1
• DOI: 10.1080/17460441.2018.1446935
• Languages: English
• ISSNs: 1746-0441

Abstract

ABSTRACT: Introduction : Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers. Areas covered : Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man. Then, the authors discuss how pharmacometabolomics gives insight into system-wide pharmacological effects and why it is a promising method to study interspecies differences. Finally, the authors advocate the application of PK/PD-metabolomics modeling to advance translational CNS drug development by discussing its opportunities and challenges. Expert opinion : It is envisioned that PK/PD-metabolomics will increase our understanding of CNS drug effects and improve translational CNS drug development, thereby increasing success rates. The successful future development of this concept will require multi-level and longitudinal biomarker evaluation over a large dose range, multi-tissue biomarker evaluation, and the generation of a proof of principle by application to multiple CNS drugs in multiple species.