|The use of the IV microtracer technique to drive formulation optimisation|
Vanessa Zann, Paul Dickinson, Wang Wang Lee, George Kirk, Owen Jones, Andy Gray, Davindera Singh Sanghera, Mark Seymour, Jo Collier, Lloyd Stevens, Julie Dent
Strategy: Use IV microtracer techniquer to de risk compounds with PK issues and drive formulation development
|Addressing the challenges of poor solubility: Rapid development and clinical evaluation of a lipid based formulation to enhance oral bioavailability of amuvatinib (MP-470)|
P.D. Scholes, J. McDermott, J. Vertommen, J-L Colin, G Choy, M Azab, R Joshi and S. Redkar
Physiochemical and biopharmaceutical properties of new chemical entities are presenting increasing challenges to successful oral drug delivery. Here we present data on amuvatinib, a novel multi-targeted tyrosine kinase inhibitor specifically designed to be a potent inhibitor of mutant c-Kit and PDGFRalpha.
|Elucidation of the Relative Bioavailability of a Drug Candidate from Different Regions of the Human Gastrointestinal Tract|
David Harris, Ph.d. , Joanne Collier, MBCHB, Alyson Connor, Ph. D. , Tomoko Freshwater, Ph. D. , David Goldfarb, Ph. D. , Ann Horowitsz Ph. D. , Xuewen Ma, Ph. D. , Paul Statkevich, Ph. D.
This poster describes a pharmacokinetic study to investigate the relative absorption of an NCE from different regions of the human gastrointestinal tract, to support potential development of a sustained-release formulation.
|Evaluation Of Single Point And IC50 Shift Assays For Measuring Time-Dependent Inhibition Of Drug Discovery Compounds|
Katie Fox, Rosey Pearson, Phillip Butler, Clive Dilworth
The aim of this study is to evaluate different assay designs, and data analysis methodology for measuring the extent of TDI for known inhibitors. We propose a reversible inhibition and TDI screening platform to cover early phase compounds, which enables accurate decisions to be made regarding development of compounds which could cause DDIs.
|GALAS Modeling Methodology Applications in the Prediction of the Drug Safety Related Properties|
Andrius Sazonovas, Remigijus Didziapetris, Justas Dapkunas, Liutauras Juska, Pranas Japertas
Early computational evaluation of drug candidate properties related to its pharmaceutical safety (such as hERG inhibition induced cardiotoxicity or CYP3A4 inhibition responsible various unwanted drug-drug interactions) is becoming increasingly important in the drug discovery process.
|Probabilistic Predictive Model of the Human Liver Microsomal Metabolism Regioselectivity|
Justas Dapkunas, Andrius Sazonovas, Pranas Japertas
Analytical identification of metabolites for a drug candidate is usually a time consuming and low-throughput task which is performed only in late drug development phases.Therefore, the ability to predict possible sites of human liver microsomal metabolism using in silico techniques would be highly beneficial for any medicinal chemist.
|Mechanistic Prediction of Volume of Distribution: The Influence of Plasma and Tissue Binding|
Kiril Lanevskij, Remigijus Didziapetris, Pranas Japertas
Plasma protein binding (usually expressed as a percentage bound fraction %PPB) and volume of distribution (Vd) are the two major parameters characterizing drug disposition in the body.
|Nitric Oxide Decreases the Expression and Activity of the Ubiquitin-Conjugating Enzyme UbcH10|
Nick D. Tsihlis, PhD, Chris S. Oustwani, BA, Ashley K. Vavra, MD, Qun Jiang, MD and Melina R. Kibbe, MD
Nitric oxide (NO) has been shown to limit the formation of neointimal hyperplasia in animal models of arterial injury. Ubiquitination proceeds via formation of thioester bonds and NO can act to disrupt those bonds. We report that NO decreases the activity and expression of UbcH10 in vitro, and decreases the expression of UbcH10 following arterial injury in vivo. Therefore, UbcH10 may be a promising therapeutic target for inhibiting neointimal hyperplasia.
|LC-MS Approaches to Profiling of Non-Radiolabelled Metabolites in Response to Recent Regulatory Changes|
Richard Clayton, Caroline Anderson, Brian Morrison and Lindsay Corfield
Following publication of the FDA MIST guidelines and revision of ICH M3, there is increasing interest in obtaining metabolic profiling data at an early stage in the development of a drug. This has led to a requirement to estimate the relative abundance of metabolites in samples prior to the synthesis of the radiolabelled compound and from a wider range of studies.