Day 1 :
Tesaro, Inc, USA
Keynote: Relative bioavailability of rolapitant tablets compared with rolapitant capsules and the effect of food on rolapitant pharmacokinetics in healthy subjects
Time : 10:30-11: 20
Xiaodong Wang is a senior director at Tesaro, Inc., an oncology-focused biopharmaceutical company in Waltham, MA, USA. He currently leads a group in Clinical Pharmacology and Drug Disposition supporting the development and regulatory submission of several drug candidates in the late phase of the Tesaro pipeline. Before joining Tesaro, he worked at several other biopharmaceutical companies, leading efforts to characterize the clinical pharmacology and pharmacometrics of small and large molecules at Bristol-Myers Squibb and Genentech. He received his PhD from the Department of Pharmaceutical Sciences, State University of New York at Buffalo, USA.
Rolapitant (VARUBI®/VARUBY®), a selective and long-acting neurokinin-1 receptor antagonist, is approved in oral tablet formulation for the prevention of delayed chemotherapy-induced nausea and vomiting in adults in the US and EU. These studies assessed the relative bioavailability of rolapitant tablet formulations compared with rolapitant capsules used in Phase 3 studies and the effect of food on rolapitant tablet pharmacokinetics (PK) in healthy subjects. An open-label, single-dose, parallel-group study was conducted in 84 healthy subjects to evaluate the relative bioavailability of two test formulations of rolapitant (high shear tablets and fluid bed tablets; each 2 x 90 mg) versus the reference capsules (4 x 45 mg). A second open-label, single-dose, parallel-group study was conducted in 80 healthy subjects to assess the effect of a high-fat meal on rolapitant PK (2 x 90 mg the intended commercial formulation of high shear tablets).
Bioavailability was similar for the test tablets verses capsules. For tablets versus the capsules, the 90% confidence intervals (CI) for the geometric mean Cmax and AUC ratios were contained within the equivalence limits of 0.80 to 1.25. For the food effect assessment, the 90% CIs for the geometric mean AUC ratios (fed/fasted) were within 0.8 to 1.25.
These data suggested that the bioavailability of rolapitant following administration as 2 x 90 mg high shear tablets and 2 x 90 mg fluid bed tablets was comparable to that following administration of 4 x 45 mg of the reference capsules. In addition, rolapitant can be taken without regard to meals
George Mason University, USA
Time : 11:20 - 12:00
He is the Director of Research at the George Mason University Biodefense Program in the Washington D.C proper. He have obtained more than $15.3 M in funding (NIH, DOD, DOE, and Keck) since my departure from NIH in 2000. He have published 196 peer-reviewed manuscripts (h index = 53), and served as an editorial board and reviewer for Retrovirology, JBC, J. Virol, Virology, NAR, 4 PLoS Journals, Cell, Molecular Cell, Nature, Medicine, and Science Translational Medicine. He am also a regular NIH study section member and have served on 141 panels since 2000.
HIV-1 infection results in a chronic illness since long-term HAART can lower viral titers to an undetectable level. However, discontinuation of therapy rapidly increases virus burden. Moreover, patients under HAART frequently develop various metabolic disorders, neurocognitive abnormalities and cardiovascular diseases. To purify vesicles, we routinely use a combination or ultracentrifugation and nanoparticle capture to concentrate our EVs from various bodily fluids for downstream assays including proteomics, Elisa, PCR, enzymatic extracellular vesicles and functional assays.
We have previously shown that exosomes containing trans-activating response (TAR) element RNA enhance susceptibility of undifferentiated naïve cells to HIV-1 infection (1-6). Up to a million copies of TAR RNA per microliter were also detected in the serum from HIV-1 infected humanized mice suggesting that TAR RNA may be stable in vivo. We recently have found another viral non-coding RNA that we termed TAR-gag which does not code for a protein, but present in the exosomes. Incubation of exosomes from HIV-1 infected cells with primary cells resulted in a dramatic increase of pro-inflammatory cytokines, IL-6 and TNF-β, indicating that exosomes containing TAR RNA could play a direct role in control of cytokine gene expression. Furthermore, the single stranded 5’ or 3’ processed stem RNA binding to TLRs activates the NF-кB pathway and regulates cytokine expression. In our most recent data, we find that the exosomes from infected cells are increased in numbers when cells are treated with specific anti-viral drugs or innate immune molecules such as IFN-a. Finally, we find that the exosomes from uninfected cells allow increased gene expression, which may explain why the latent cells show transcriptional leakiness.
Our results directly indicate that HIV viral release and exosome release have overlapping biogenesis pathways including the ESCRT pathway. Similar results are also seen from other neuro-tropic RNA viral infections including HTLV-1, Ebola, RVFV, and Zika infection which will be discussed. Therefore targeting these particles may be a method to lower overall viral burden in infected immunocompromised hosts.