Revealing the Neuroendocrine Response After Remoxipride Treatment Using Multi-Biomarker Discovery and Quantifying It by PK/PD Modeling

Abstract

Abstract.To reveal unknown and potentially important mechanisms of drug action, multibiomarker discovery approaches are increasingly used. Time-course relationships between drug action and multi-biomarker profiles, however, are typically missing, while such relationships will provide increased insight in the underlying body processes. The aim of this study was to investigate the effect of the dopamine D2 antagonist remoxipride on the neuroendocrine system. Different doses of remoxipride (0, 0.7, 5.2, or 14 mg/kg) were administered to rats by intravenous infusion. Serial brain extracellular fluid (brainECF) and plasma samples were collected and analyzed for remoxipride pharmacokinetics (PK). Plasma samples were analyzed for concentrations of the eight pituitary-related hormones as a function of time. A Mann-Whitney test was used to identify the responding hormones, which were further analyzed by pharmacokinetic/ pharmacodynamic (PK/PD) modeling. A three-compartment PK model adequately described remoxipride PK in plasma and brainECF. Not only plasma PRL, but also adrenocorticotrophic hormone (ACTH) concentrations were increased, the latter especially at higher concentrations of remoxipride. Brain-derived neurotropic factor (BDNF), follicle stimulating hormone (FSH), growth hormone (GH), luteinizing hormone (LH), and thyroid stimulating hormones (TSH) did not respond to remoxipride at the tested doses, while oxytocin (OXT) measurements were below limit of quantification. Precursor pool models were linked to brainECF remoxipride PK by E max drug effect models, which could accurately describe the PRL and ACTH responses. To conclude, this study shows how a multi-biomarker identification approach combined with PK/PD modeling can reveal and quantify a neuroendocrine multi-biomarker response for single drug action.

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

“…A potential and valuable role of microdialysis can be to use the technique as a local sampling device in metabolomics studies, thereby finding fingerprints of disease and the pharmacological interventions, and relate this to drug concentrations in the same tissue(s). However, such studies are still sparse and require state-of-the-art analytical equipment (4,5). Modeling, being an important part in systems pharmacology analysis, has been used rather extensively in microdialysis studies to refine the raw data and interpret the findings (1)(2)(3)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

“…With integrated PK-PD analyses, multiple in vivo potencies for these responses were determined, associated with several biological pathways. These included the dopamine metabolism, the adrenaline metabolism, the serine-glycine-threonine metabolism, and the serotonin metabolism [18,19].…”

Exploring Kp,uu,BBB Values Smaller than Unity in Remoxipride: A Physiologically-Based CNS Model Approach Highlighting Brain Metabolism in Drugs with Passive Blood-Brain Barrier Transport

“…The best-fitting models identified passive BBB transport, with the need to include brain elimination (Stevens et al, 2011; van den Brink et al, 2017a). In other words, there was a discernible loss of remoxipride from the brain that did not return to plasma (van den Brink et al, 2017b), strongly suggested the involvement of brain metabolism in the elimination process.…”