|In silico Identification of Metabolic Soft Spots: Case Study Using ACD/ADME Suite Software|
Justas Dapkunas, Andrius Sazonovas, Remigijus Didziapetris and Pranas Japertas
Metabolic stability, determined in liver microsomes, is one of the primary assays used in early drug discovery. A key factor limiting compound half-life is the cytochrome P450 mediated metabolism. High clearance by these enzymes implies a higher and more frequent dosing as well as poses a risk for individual variations in exposure.
|Differential Toxicities of Kinase Inhibitors (KI) on Bone Marrow Progenitors from Different Species|
Clarke, E. and Dos Santos, G.
Myelotoxicity is often a side effect of kinase inhibitors. We reported a correlation (R2 = 0.81) between in vitro human CFU-GM IC50 values and clinical neutropenia. When these values were obtained from other species, non-human primate and dog values compared well with human data, but rat and mouse IC50 values differed significantly. This suggests rodent assays may not accurately predict toxicity to the human hematopoietic system.
|Development of Two Novel High-throughput Colorimetric Toxicity Detection Assays|
Kimberly Lubell and Joseph Krebs
The MaxDiscovery Aspartate Transaminase (AST) and Lactate Dehydrogenase (LDH) Color Endpoint Assays permit visible detection of in vivo toxicity using only 5 µL of serum from rodents or other mammals. These novel assays employ simplified endpoint analysis to offer high sensitivity, low detection limits and the ability to use a visible plate reader.
|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.