Core C, Quantitative Pharmacology and Biostatistics, will provide pharmacology and biostatistics support to all projects in the application. The Core is composed of three complementary components (quantitative analysis, modeling/simulation and biostatistics/data management) that serve the five Core aims.
Aim 1 : To develop bioanalytical methods to detect drug and biomarker exposure. Develop analytical methods to detect NKIR antagonist drug candidates in various biologic matrices in human and animal experiments. Develop biomarker assays (substance P and other neurokinins) to support both preclinical and clinical projects.
Aim 2 : To identify potential novel biomarkers of drug activity, subject characteristics correlated to therapeutic response and time-dependent markers of disease progression via metabolomic and metabonomic support. Determine metabolic differences in healthy volunteers, depressed and HIV-infected patients (with and without depression);assess metabolic time course in Neuro AIDS patients.
Aim 3 : To provide in silico ADME screens and decision criteria for drug candidates. Assess and rank "druggability" metrics generated from in vitro attributes and physiochemical data from HTS. Assess drug interaction potential for candidate combinations to be studied In animal and human trials.
Aim 4 : To provide pharmacokinetic (PK) and pharmacodynamic (PD) support for dose targeting in animal and human trials;develop PK, PD and disease progression models to define the therapeutic window for clinical candidates. PK/PD modeling to support dose selection for patient trials. Population-based PK/PD modeling to understand sources of variation in drug kinetics and viral dynamics. Disease progression modeling incorporating metabonomic indices along with clinical response and disease status. Clinical trial simulation to facilitate optimal sampling and trial design.
Aim 5 : To provide information systems, data management and biostatistics support to all projects and cores. Assist in the design and interpretation of preclinical/clinical experiments;support sample size requirements. Design and maintain a database to accommodate projects and cores. Manage, verify and maintain data; implement data sharing plan.
The Pharmacology and Biostatistics Core is a crucial component ofthe IPCP. The main role of this core is to support the projects and other cores in developing and using bioanalytical methods for assessing NKIR antagonist therapeutic activity with regard to neuroAIDS. The core will also support the projects and other cores in clinical trial management and data analysis.
|Barrett, Jeffrey S; Bajaj, Gaurav; McGuire, Jennifer et al. (2014) Modeling and simulation approach to support dosing and study design requirements for treating HIV-related neuropsychiatric disease with the NK1-R antagonist aprepitant. Curr HIV Res 12:121-31|
|Tuluc, Florin; Meshki, John; Spitsin, Sergei et al. (2014) HIV infection of macrophages is enhanced in the presence of increased expression of CD163 induced by substance P. J Leukoc Biol 96:143-50|
|Schwartz, Lynnae; Spitsin, Sergei V; Meshki, John et al. (2013) Substance P enhances HIV-1 infection in human fetal brain cell cultures expressing full-length neurokinin-1 receptor. J Neurovirol 19:219-27|
|Spitsin, Sergei; Tuluc, Florin; Meshki, John et al. (2013) Analog of somatostatin vapreotide exhibits biological effects in vitro via interaction with neurokinin-1 receptor. Neuroimmunomodulation 20:247-55|
|Barrett, Jeffrey S; McGuire, Jennifer; Vezina, Heather et al. (2013) PET measurement of receptor occupancy as a tool to guide dose selection in neuropharmacology: are we asking the right questions? J Clin Psychopharmacol 33:725-8|
|Spitsin, Sergei; Stevens, Kathleen E; Douglas, Steven D (2013) Expression of substance P, neurokinin-1 receptor and immune markers in the brains of individuals with HIV-associated neuropathology. J Neurol Sci 334:18-23|
|Khan, Mohammad M; Douglas, Steven D; Benton, Tami D (2012) Substance P-neurokinin-1 receptor interaction upregulates monocyte tissue factor. J Neuroimmunol 242:1-8|
|Meshki, John; Douglas, Steven D; Hu, Mingyue et al. (2011) Substance P induces rapid and transient membrane blebbing in U373MG cells in a p21-activated kinase-dependent manner. PLoS One 6:e25332|
|Douglas, Steven D; Leeman, Susan E (2011) Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Ann N Y Acad Sci 1217:83-95|
|Monaco-Shawver, Linda; Schwartz, Lynnae; Tuluc, Florin et al. (2011) Substance P inhibits natural killer cell cytotoxicity through the neurokinin-1 receptor. J Leukoc Biol 89:113-25|