Workshop: Challenges and Opportunities in ADME-Tox

Paul Walker, Cyprotex

Cardiotox; beyond the traditional ion channels, using omics and other predictive cardio models

In this presentation, we discuss the latest in vitro methods for assessing structural and functional cardiotoxicity and how these can be applied in improving translation to humans. In addition, advanced techniques such as transcriptomics will be presented along with a demonstration of their value in providing a better mechanistic understanding of cardiotoxic effects.

Markus Trunzer, PK Sciences, Novartis

Clearance IVIVE with highly plasma protein bound molecules

In vivo extrapolation of clearance from in vitro assays is notoriously difficult with highly plasma protein bound molecules. To simplify the problem, we focused on permeable compounds; an analysis of about 2000 low dose rat PK experiments showed that while in vivo clearance is predicted within 3-fold in 70% of the cases for neutrals and bases this falls to around 35% for acids. The main reason for this difference is the lower plasma fu values of acidic molecules. In the classical well stirred model, the binding effect is eventually over corrected, leading to underpredictions. We challenged implicit assumptions that are made in the standard approach and proposed an alternative assay design to account for protein binding.

Ferran Sanchez, Sciex

Technology drivers for drug discovery

Within this talk we will discuss two different technologies:
First, how a new orthogonal fragmentation mode combined with a high sensitive QTOF instrument can accelerate drug metabolite characterization. 
Second, we will get into HT-ADME studies using Acoustic Ejection Mass Spectrometry (AEMS) on the Echo® MS system. We will discuss how to accelerate and increase the number of compounds to be tested by an order of magnitude developing and running a suite of metabolic stability assays using both LC-MS/MS and the Echo® MS system and compare the workflows.

Ruben De Kanter, PK Sciences, Novartis

Thoughts about lack of oral exposure

Discovery compounds are described that show poor exposure after oral dosing to rats. The usual suspects for low bioavailability were excluded: permeability and solubility were ‘good’ and in vivo i.v. blood clearance was ‘low to medium’. 
The subject for discussion is to think about alternative in vitro assays that could be helpful to understand the lack of oral exposure.

Nada Abla Geiser, MMV

PBPK modelling to support anti-malarial drug development

Medicines for Malaria Venture (MMV) is a product development partnership whose mission is to reduce the burden of malaria in disease-endemic countries by discovering, developing, and delivering new, effective, and affordable antimalarial drugs. 
This presentation will focus on the use of physiologically based pharmacokinetic (PBPK) modelling to optimise the use of existing antimalarials and to support the development of new combinations, by predicting potential drug-drug interactions and pharmacokinetics in special populations. In order to develop reliable models, emphasis has been placed on generating robust in vitro DMPK data to fully characterise the properties of each compound.

Michael McCullagh, Waters Corporation

Improving metabolite identification with faster and more confident identifications with part per billion mass accuracy

A non-targeted data independent (DIA) screening assay for small molecules analysis was performed. The UPLC™ MS (ultra-performance liquid chromatography mass spectrometry) accurate mass measurement specificity attained with the SELECT SERIES MRT, built with state-of-the-art Multi Reflecting Time-of-Flight (MRT) technology was assessed.
We discuss how the ppb mass accuracy achieved can be used to improve data analysis efficiency and identification confidence in small molecule application research.

Tim Sharpe, Biophysics Facility, University of Basel

Comparing techniques for quantifying macromolecular mass and size distributions

The methods for quantifying macromolecular mass and size distributions that we use in our Biophysics Facility at the Biozentrum, University of Basel will be discussed. Specifically, the technical basis, advantages and disadvantages of size-exclusion-coupled multi-angle static light scattering (SEC-MALS), dynamic light scattering (DLS), analytical ultracentrifugation (AUC), and mass photometry (Refeyn), when applied to a variety of different academic structural biology projects. These techniques offer different and sometimes complementary sets of mass and size information over a concentration range of 10^-9 to 10^-3 M, with significantly different material, time, and cost requirements.

Phil Butler, Cyprotex

DMPK strategies for PROTACs and peptides

New therapeutic modalities offer an exciting opportunity to overcome the challenge of utilising biological targets once considered ‘undruggable’ using traditional small molecules. However, the physicochemical properties of many new modalities mean that standard DMPK screening approaches are either unsuitable or irrelevant, and experimental design, screening strategies and analytical methods need to be considered carefully. In this presentation, we discuss the application of modified DMPK screening strategies for new modalities, with a particular focus on PROTACs and peptides.

Simon Wood, Cyprotex

Analytical workflows for beyond the rule of five chemistry in drug discovery

In the drug discovery environment there is typically a requirement to measure the dosed drug and potential metabolites as an end point in many ADME-Tox assays. Generic small molecule analytical approaches may not always be successful when applied to beyond rule of five (bRo5) chemistries due to their specific physico- chemical properties which may in turn lead to analytical and assay challenges. In this presentation we discuss the potential challenges and propose that generic starting points may be possible to speed up method development and increase the chance of analytical success.
Case studies for analytical workflows, focusing on PROTACs and peptides are presented showing how challenging physico chemical properties can manifest themselves and what analytical tools are available to provide solutions.