Core B Abstract: Pharmacokinetic analyses are required throughout preclinical and clinical studies to support the efficacy and safety studies as well as to provide basis for the design of subsequent clinical studies in humans. In addition, valid bioanalytical methods are required to quantify the drugs of interest, which allow the generation of accurate data to be used in the pharmacokinetics analysis. Therefore, we have created a core (Core B) to provide bioanalytical and pharmacokinetic (PK) support throughout the preclinical studies proposed in Projects 1, 2 and 3. Core B serves dual purposes: (i) provide bioanalytical and PK support to the preclinical development of nanoART, and (ii) characterize the kinetics and the mechanisms of the extent of drug transport across the blood brain barrier (BBB) and lymphatics. Throughout the project, mice will receive single and multiple dosing regimens of individual or combinational nanoART drugs to characterize reference PK parameters. Starting doses in mice will be scaled from the dose recommended in humans based on body- surface area (shape factor) normalization. PK, tissue distribution, BBB penetration, and toxicity will be compared between the nanoART and free drug. Next, nanoART, control nanodrugs other than ART and free ART will be administered to infected humanized mice as a part of a dose efficacy study. Plasma and target tissue concentrations will be determined. PK studies similar to that in mice will be performed in uninfected monkeys. Starting doses in monkeys will also be scaled from the dose recommended in humans based on body-surface area (shape factor) normalizations. PK parameters and linearities will be assessed. The multiple dosing efficacy studies will aim to achieve and maintain systemic exposure levels similar to that recommended in humans without exceeding peak exposure levels. The multiple dosing regimens will be designed from the single dose PK. Hematology and chemistry panels will be monitored, and plasma drug concentrations measured for up to 14 weeks following multiple drug administration (with Projects 1 and 2). The long-term goal is to develop injectable nanoART for human use. If successful the work could lead to novel formulations that improve medication adherence, and thereby therapeutic outcomes. Novel treatment applications will include enhanced penetration into viral reservoirs such as the central nervous and lymphatic systems.
| Ottemann, Brendan M; Helmink, Austin J; Zhang, Wenting et al. (2018) Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities. Biomaterials 185:174-193 |
| Zhou, Tian; Su, Hang; Dash, Prasanta et al. (2018) Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials 151:53-65 |
| Kevadiya, Bhavesh D; Ottemann, Brendan M; Thomas, Midhun Ben et al. (2018) Neurotheranostics as personalized medicines. Adv Drug Deliv Rev : |
| Gautam, Nagsen; Lin, Zhiyi; Banoub, Mary G et al. (2018) Simultaneous quantification of intracellular lamivudine and abacavir triphosphate metabolites by LC-MS/MS. J Pharm Biomed Anal 153:248-259 |
| Zhou, Tian; Lin, Zhiyi; Puligujja, Pavan et al. (2018) Optimizing the preparation and stability of decorated antiretroviral drug nanocrystals. Nanomedicine (Lond) 13:871-885 |
| Kiyota, Tomomi; Machhi, Jatin; Lu, Yaman et al. (2018) Granulocyte-macrophage colony-stimulating factor neuroprotective activities in Alzheimer's disease mice. J Neuroimmunol 319:80-92 |
| McMillan, JoEllyn M; Cobb, Denise A; Lin, Zhiyi et al. (2018) Antiretroviral Drug Metabolism in Humanized PXR-CAR-CYP3A-NOG Mice. J Pharmacol Exp Ther 365:272-280 |
| McMillan, JoEllyn; Szlachetka, Adam; Zhou, Tian et al. (2018) Pharmacokinetic testing of a first generation cabotegravir prodrug in rhesus macaques. AIDS : |
| Montenegro-Burke, J Rafael; Woldstad, Christopher J; Fang, Mingliang et al. (2018) Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress. Mol Neurobiol : |
| Olson, Katherine E; Bade, Aditya N; Namminga, Krista L et al. (2018) Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. J Neurovirol 24:398-410 |
Showing the most recent 10 out of 141 publications
