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.
Pharmacolog