Modelling hemodynamics regulation in rats and dogs to facilitate drugs safety risk assessment.

Pharmaceutical companies routinely screen compounds for hemodynamics related safety risk. secondary pharmacology is initially used to prioritize compounds while studies are later used to quantify and translate risk to humans. This strategy has shown limitations but could be improved via the incorporation of molecular findings in the animal-based toxicological risk assessment.

Predicting progression-free survival from measurable residual disease in chronic lymphocytic leukemia.

Association between measurable residual disease (MRD) and survival outcomes in chronic lymphocytic leukemia (CLL) has often been reported. However, limited quantitative analyses over large datasets have been undertaken to establish the predictive power of MRD. Here, we provide a comprehensive assessment of published MRD data to explore the utility of MRD in the prediction of progression-free survival (PFS).

Opportunities for Quantitative Translational Modeling in Oncology.

A 2-day meeting was held by members of the UK Quantitative Systems Pharmacology Network () in November 2018 on the topic of Translational Challenges in Oncology.

Modelling of the cancer cell cycle as a tool for rational drug development: A systems pharmacology approach to cyclotherapy.

The dynamic of cancer is intimately linked to a dysregulation of the cell cycle and signalling pathways. It has been argued that selectivity of treatments could exploit loss of checkpoint function in cancer cells, a concept termed "cyclotherapy". Quantitative approaches that describe these dysregulations can provide guidance in the design of novel or existing cancer therapies.

Combenefit: an interactive platform for the analysis and visualization of drug combinations.

Motivation: Many drug combinations are routinely assessed to identify synergistic interactions in the attempt to develop novel treatment strategies. Appropriate software is required to analyze the results of these studies.

Results: We present Combenefit, new free software tool that enables the visualization, analysis and quantification of drug combination effects in terms of synergy and/or antagonism.

An automated fitting procedure and software for dose-response curves with multiphasic features.

In cancer pharmacology (and many other areas), most dose-response curves are satisfactorily described by a classical Hill equation (i.e. 4 parameters logistical).

A new classifier-based strategy for in-silico ion-channel cardiac drug safety assessment.

There is currently a strong interest in using high-throughput in-vitro ion-channel screening data to make predictions regarding the cardiac toxicity potential of a new compound in both animal and human studies. A recent FDA think tank encourages the use of biophysical mathematical models of cardiac myocytes for this prediction task. However, it remains unclear whether this approach is the most appropriate.

hERG inhibitors with similar potency but different binding kinetics do not pose the same proarrhythmic risk: implications for drug safety assessment.

Introduction: Since the discovery of the link that exists between drug-induced hERG inhibition and Torsade de Pointes (TdP), extreme attention has been given to avoid new drugs inhibiting this channel. hERG inhibition is routinely screened for in new drugs and, typically, IC50 values are compared to projected plasma concentrations to define a safety margin.

Methods And Results: We aimed to show that drugs with similar hERG potency are not uniformly pro-arrhythmic-this depends on the drug binding kinetics and mode of action (trapped or not) rather than the IC50 value only.

High-throughput screening of drug-binding dynamics to HERG improves early drug safety assessment.

The use of computational models to predict drug-induced changes in the action potential (AP) is a promising approach to reduce drug safety attrition but requires a better representation of more complex drug-target interactions to improve the quantitative prediction. The blockade of the human ether-a-go-go-related gene (HERG) channel is a major concern for QT prolongation and Torsade de Pointes risk. We aim to develop quantitative in-silico AP predictions based on a new electrophysiological protocol (suitable for high-throughput HERG screening) and mathematical modeling of ionic currents.