Year: 2010
Prediction of Vss and Tissue Concentration-time Profiles for Four Benzodiazepines Using Physicochemical, In Vitro and Experimental Data in Rat Using a Mechanistic PBPK Model
3D-QSAR and Molecular Docking Studies on Derivatives of MK-0457, GSK1070916 and SNS-314 as Inhibitors Against Aurora B Kinase
Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of … Continued
3D-QSAR Analysis of Human Immunodeficiency Virus Entry-1 Inhibitors by CoMFA and CoMSIA
3D-QSAR studies namely CoMFA, CoMFA region focusing and CoMSIA have been carried out on a series (36 compounds) of HIV-1 entry inhibitors. An alignment rule for the compounds was defined using Distill in SYBYL® 7.3. Models were validated using a data set obtained by dividing the data set into a training set and test set … Continued
Determination of a Quantitative Relationship Between Hepatic CYP3A5*1/*3 and CYP3A4 Expression for Use in the Prediction of Metabolic Clearance in Virtual Populations
The creation of virtual populations allows the estimation of pharmacokinetic parameters, such as metabolic clearance in extreme individuals rather than the ‘average human’. Prediction of variability in metabolic clearance within genetically diverse populations relies on understanding the covariation in the expression of enzymes. A number of statistically significant positive correlations have been observed in the … Continued
Development of a Modeling Framework to Simulate Efficacy Endpoints for Motesanib in Thyroid Cancer Patients
To develop a modeling framework that simulates clinical endpoints (objective response rate and progression-free survival) to support development of motesanib. The framework was evaluated using results from a phase 2 study of motesanib in thyroid cancer. Models of probability and duration of dose modifications and overall survival were developed using data from 93 patients with … Continued
Population Pharmacokinetic/Pharmacodynamic Modeling for the Time Course of Tumor Shrinkage by Motesanib in Thyroid Cancer Patients
To develop a population pharmacokinetic/pharmacodynamic model describing the relationship between motesanib exposure and tumor response in a phase 2 study of motesanib in patients with advanced differentiated thyroid cancer or medullary thyroid cancer. Data from patients (n = 184) who received motesanib 125 mg once daily were used for population pharmacokinetic/pharmacodynamic modeling. Motesanib concentrations were … Continued
Incorporating Human Dosimetry and Exposure into High-throughput In Vitro Toxicity Screening
Many chemicals in commerce today have undergone limited or no safety testing. To reduce the number of untested chemicals and prioritize limited testing resources, several governmental programs are using high-throughput in vitro screens for assessing chemical effects across multiple cellular pathways. In this study, metabolic clearance and plasma protein binding were experimentally measured for 35 ToxCast phase I chemicals. … Continued
Prediction of Human Intestinal Metabolism of CYP3A Substrates Using the Advanced, Dissolution, Absorption and Metabolism (ADAM) Model
Randomised, Parallel-group, Multicenter, Multinational Phase 2 Study Comparing Edoxaban, an Oral Factor Xa Inhibitor, with Warfarin for Stroke Prevention in Patients with Atrial Fibrillation
The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with non-valvular atrial fibrillation (AF). In this 12-week, parallel-group, multicentre, multinational study, 1,146 patients with AF and risk of stroke were randomised to edoxaban 30 mg qd, 30 mg bid, 60 mg qd, or … Continued