Multi-biomarker pharmacokinetic-pharmacodynamic relationships of central nervous systems active dopaminergic drugs

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Multi-biomarker pharmacokinetic-pharmacodynamic relationships of central nervous systems active dopaminergic drugs

Type: Doctoral Thesis
Title: Multi-biomarker pharmacokinetic-pharmacodynamic relationships of central nervous systems active dopaminergic drugs
Author: Brink, W.J. van den
Issue Date: 2018-11-21
Keywords: Biomarkers
Central Nervous System
Dopamine
Pharmacometabolomics
PK/PD modeling
Neuroendocrine System
Systems Pharmacology
Abstract: Discovery and development of Central Nervous System (CNS) drugs is hampered by high attrition rates. One of the reasons is the lack of blood-based biomarkers that represent the interaction between the drug and the neurological systems of interest. Here we present a systems-pharmacology approach that combines a multi-biomarker approach (e.g. metabolomics) with pharmacokinetic/pharmacodynamic (PK/PD) modeling to reveal quantitative pharmacological characteristics that are relevant to dopaminergic drug action. Moreover, we set out to identify biomarkers that can be obtained from the blood as non-invasive sampling site. In the first section of this thesis the methodology is introduced in the context of translational CNS drug development. Moreover, a systematic search is performed to available biomarkers of dopaminergic drug action. Then, in the second part, the multi-biomarker PK/PD approach is applied to biomarkers from the neuroendocrine system as connection between brain and blood. In the third section, the methodology is developed using the simultaneous, time-resolved metabolomics response in brain extracellular fluid and plasma. By applying multi-biomarker PK/PD modeling we revealed quantitative pharmacological characteristics of dopaminergic drugs with regard to multiple biological processes. Moreover, we identified potential blood-based biomarkers of dopaminergic effect in the brain.
Promotor: Supervisor: Graaf P.H. van der, Hankemeier T., Lange E.C.M. de
Faculty: Faculty of Science
University: Leiden University
Uri: urn:isbn:9789463324182
Handle: http://hdl.handle.net/1887/65997
 

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