The Bioanalytical and DMPK Core will provide high throughput in vitro screening and LC/MS/MS bioanalytical support in the following discovery and preclinical development Projects (1, 2) identified within this application: 1) perform the Tier 1 DMPK screening of;2) perform the rodent PK assessment and subsequent bioanalysis of mGlu5 NAM discovery compounds as well as assess the PK properties of compounds testing externally in dogs and nonhuman primates;and 3) perform the bioanalysis of biological media originating from the behavioral pharmacology assessment of mGIU5 discovery candidates in rodent models of depression, as well as establish PK/PD relationships of said studies. Built with key personnel possessing experience from the pharmaceutical industry, specifically from drug metabolism and pharmacokinetic (PK) research and development experience, the Core will aid in PK study design, coordinate the receipt and storage of biological media samples originating from preclinical pharmacology, definitive PK studies and nonpivotal toxicity studies, as well as plasma and urine samples originating from Phase 1 clinical studies. The Core will also implement the Tier 1 DMPK screen, including subsequent in vitro bioanalysis. The DMPK scientist will adopt a contemporary approach to LC/MS/MS based bioanalysis employing state-of-the-art mass spectrometry and liquid chromatography equipment and an adherence to regulatory guidances appropriate for the nonGLP PK studies. Finally, Dr. Daniels and his DMPK team will perform PK analysis of the data employing industry-standard software capable of modeling time concentration profiles generated from nonclinical studies.

Public Health Relevance

The Bioanalytical and DMPK Core will provide assistance to the principal investigators (Pis) linked to the respective Projects within the application, specifically through the screening of mGIUs discovery NAMs for DMPK attributes and exposure determination from investigations in rat models of depression. By providing PK expertise across this interdisciplinary set of Projects, the DMPK Core will be able to influence the successful transition of lead mGIUs NAM compounds from a discovery stage to the preclinical development setting, an experience certain to facilitate similar transitions of neuropharmacology programs within the VCNDD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZMH1-ERB-C)
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Vanderbilt University Medical Center
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