Blood‐Based Biomarkers of Quinpirole Pharmacology: Cluster‐Based PK/PD and Metabolomics to Unravel the Underlying Dynamics in Rat Plasma and Brain

Abstract

A key challenge in the development of central nervous system drugs is the availability of drug target specific blood‐based biomarkers. As a new approach, we applied cluster‐based pharmacokinetic/pharmacodynamic ( PK / PD ) analysis in brain extracellular fluid (brain ECF ) and plasma simultaneously after 0, 0.17, and 0.86 mg/kg of the dopamine D 2/3 agonist quinpirole ( QP ) in rats. We measured 76 biogenic amines in plasma and brain ECF after single and 8‐day administration, to be analyzed by cluster‐based PK / PD analysis. Multiple concentration‐effect relations were observed with potencies ranging from 0.001–383 nM . Many biomarker responses seem to distribute over the blood‐brain barrier (BBB). Effects were observed for dopamine and glutamate signaling in brain ECF , and branched‐chain amino acid metabolism and immune signaling in plasma. Altogether, we showed for the first time how cluster‐based PK / PD could describe a systems‐response across plasma and brain, thereby identifying potential blood‐based biomarkers. This concept is envisioned to provide an important connection between drug discovery and early drug development.

Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges

“…Machine learning, other artificial intelligence algorithms, optimal design of experiments, and mathematical techniques for dimensionality reduction will prove invaluable in identifying the biomarkers. 118 However, the findings of such approaches are as good as the quality of the training set data, which are often less than ideal in clinical situations. In many cases, these approaches yield correlations and associations but not necessarily causal relationships A mechanism-based QSP model can partially uncover causality by integrating formalized domain expertise on the pathways or circuits identified in these analyses, as proposed previously.…”