Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics

Brink, W.J. van den; Hankemeier, T.; Graaf, P.H. van der; Lange, E.C.M. de (2018)

Article / Letter to editor

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. INTRODUCTION

• All authors: Brink, W.J. van den; Hankemeier, T.; Graaf, P.H. van der; Lange, E.C.M. de
• Date: 2018-07-01
• Journal: Expert Opinion on Drug Discovery
• Volume: 13
• Issue: 6
• Pages: 539 - 550
• DOI: doi:10.1080/17460441.2018.1446935