Exhibitor Showcases
9:45 - 10:00 am | Monday, September 11
Admescope
In vitro – in vivo Correlation of Antisense Oligonucleotide Metabolism
Dr. Ari Tolonen, CSO & Head of in vitro Metabolism and Biotransformations
Results will be presented from metabolite profiling studies performed with two phosphorothioate backbone ASOs using various liver and kidney derived in vitro models and rat in vivo experiments, to compare the in vitro – in vivo correlation.
Over the past decade, there has been an increased interest towards oligonucleotide-based therapies. Several generations of antisense oligonucleotides (ASOs) have been introduced as drug candidates, with structural modifications in their RNA backbone and ribose units, aimed at optimizing their affinity towards the target, as well as their distribution, metabolism, and pharmacokinetics.
ASOs are generally metabolized to shorter oligomers by various exo- and endonucleases in several tissues. As the backbone-modified ASOs typically have a high distribution to liver and kidney, the metabolism occurring in these organs plays a major role in their elimination. Biotransformation data is typically needed for regulatory health agencies in early clinical stage development, and with the lack of widely accepted in vitro models for ASO metabolism studies, the data is often collected by analysis of samples from general toxicity studies.
Metabolite profiling studies were performed with two phosphorothioate backbone ASOs, i.e. alicaforsen and ribose 2-methoxyethyl-modified gapmer volanesorsen, using various liver and kidney derived in vitro models and rat in vivo experiments, and results will be presented to compare the in vitro – in vivo correlation.
A high number of metabolites were detected for both ASOs, their number and relative abundances generally being the highest in the in vivo liver and kidney samples and the lowest in the in vitro samples. No clear differences between rat and human in vitro experiments were found, but slightly different metabolite profiles between in vitro hepatic and renal models were observed. The in vitro experiments predicted the most abundant in vivo plasma, liver and kidney metabolites, formed via deletions from 3’ n-terminal, better for alicaforsen than for 2’- MOE-modified volanesorsen. The hepatic and renal in vitro models show variable correlation to rat in vivo metabolite profiles. To reduce the use of animals in research and to enable better early-stage prediction of oligonucleotide therapeutics in vivo metabolism, novel hepatic and renal in vitro assays are needed.
12:15 - 12:45 pm | Monday, September 11
Solvo
Solving major pitfalls of MDR1 species differences and MDR1/MDR3 substrate specificity overlap with novel in vitro monolayer systems.
Marko Andric, Senior Business Development, DMPK, Charles River
Investigation of ABC Efflux transporters in monolayer systems to predict substrate specificity and inhibition profiles has been a major challenge due to inconsistencies in assay conditions, complexity of in vitro models, differences in endogenous transporter expression and drug concentration at the binding site. Differences in expression levels between tissues and species together with ligand specificities between species are already well documented for ABCB1 (MDR1). Currently, inconsistencies in in vitro assay conditions applied by different laboratories cause further challenges in the prediction of MDR1 substrate specificity to predict human blood brain barrier (BBB) penetration and inhibitory profiles across species. Another important ABC transporter, ABCB4 (MDR3), has been less studied since it shares up to 76% identity and 86% similarity in the amino acid sequence with MDR1.
Although MDR3 activity and drug interaction is challenging to characterize in vitro, MDR3 transport has been shown relevant in DILI prediction and elucidating the mechanism of drug induced cholestasis, activity and drug interaction. SOLVO’s Research and Development team have successfully addressed these challenges by establishing canine Abcb1-knockout Madin-Darby canine kidney (MDCKII) cell lines to assess BBB transport properties as well as species differences across mouse, rat, cyno and human MDR1 transport. Using the same cellular background, we have established a novel non-hepatocyte based human MDR3 assay to screen the inhibition potential of chemical entities with higher sensitivity and superior system for MDR3 substrate identification.
2:15 - 2:45 pm | Monday, September 11
Discovery Life Sciences
Gentest® In Vitro Preclinical Solutions at Discovery
David Randle, PhD, VP Preclinical Services, Discovery Life Sciences
This presentation will showcase the comprehensive portfolio of Gentest® In Vitro Preclinical Solutions at Discovery Life Sciences. The Gentest® brand now provides access to one of the world's largest inventories of hepatocytes, tissue fractions, and recombinant enzymes, complemented by leading-edge service technologies. In this presentation, we will delve into the details of this unique innovation engine and its pivotal role in supporting ADME and toxicology scientists. By facilitating the generation of crucial data, our solutions empower the scientists to make informed decisions that significantly impact drug developments.
9:45 - 10:00 am | Tuesday, September 12
Javelin
A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics and Toxicology Applications
Murat Cirit, PhD is a bioengineer and the co-founder & CEO of Javelin Biotech. His career spans the design and validation of tissue chip models for drug discovery to the development of computational algorithms for in vitro in vivo translation. He brings an interdisciplinary approach to develop human centric preclinical drug discovery platforms for a deeper understanding of biological, physiological, and pharmacological processes.
A crucial step in lead selection during drug development is accurate estimation and optimization of hepatic clearance and toxicology applications using in vitro methods. However, current methods are limited by factors such as lack of physiological relevance, short culture/incubation times that are not consistent with drug exposure patterns in patients, use of drug absorbing materials, and evaporation during long-term incubation.
To address these technological needs, Javelin Biotech developed a novel milli-fluidic human Liver Tissue Chip (LTC) that was designed with continuous media recirculation and optimized for hepatic cultures using human primary hepatocytes. Learn about the features and characteristics of the LTC, including high reproducibility, long-term CYP activity, and gene and mRNA expression. Javelin will present results from key applications, including clearance, DDI, and DILI, and share how you can adopt the LTC Platform in your lab.
12:15 - 12:45 pm | Tuesday, September 12
Pharmaron
In silico Approaches to DMPK – A Journey Through the Ages
Barry Jones
Over the past 30 years or so the utilisation of a wide variety of in silico methods has had an evolving influence on DMPK and by association to drug discovery and development. Here, some of these methods will be discussed along with their impact from the perspective of my DMPK career and the evolution of DMPK science through this period.
The initial focus will be on the impact of structural modelling and structure-based drug design from early cytochrome P450 substrate overlays and pharmacophore models through to the impact of x-ray crystal structures and beyond into the cryoEM structures of transporters.
Beyond chemical structure related modelling the advent and impact of in silico techniques, such as PBPK and PKPD modelling, will also be discussed in the context of the increasing impact on drug discovery, notably in support of dose prediction, as well as the impact on the increasing breadth of the capabilities of DMPK scientists.
Finally, the quantitative prediction of ADME and physiochemical properties is now recognised as an essential element in the design of new molecules ensuring holistic drug-like properties are understood at the outset. QSAR models have long been the focus of cheminformatics but recent advances in machine learning methodologies have reinvigorated this field. The advantages and pitfalls of these models will be presented. Thoughts on key areas for further model improvements will also be discussed.
9:45 - 10:00 am | Wednesday, September 13
Pharmalegacy
Swift Solutions to Complex Challenges in DMPK, Pharmacodynamics, and Toxicology
Baomin Xin, Senior Vice President of DMPK and Bioanalytical
This scientific presentation provides an in-depth exploration of PharmaLegacy's DMPK and bioanalytical services, showcasing the company's comprehensive capabilities, industry-best lead times for NHP studies, and remarkable acceleration of project timelines.
Beginning with a company introduction, the presentation delves into essential aspects of Pharmacokinetics and Bioanalysis, highlighting ADME analysis of metabolic stability and DDI as well as permeability and MetID.
The presentation extends to Discovery Toxicology, along with insights into DRF assessment. Finally, the focus shifts to PK/PD relationships and how PharmaLegacy drastically shortens drug discovery timelines.
12:15 - 12:45 pm | Wednesday, September 13
Q2 Solutions
ADME screening, Met ID to Method Validation: BioA Case studies demonstrating Drug Discovery process
Tom Fleischmann, Toby Magers, Nick Ingram, Brian Engel, Prakash Bhosale
Drug discovery process starts with the evaluation of in vitro properties and in vivo plasma/tissue exposures which help us to optimize ADME patterns for potential drug candidates and assess risk associated with metabolism and drug-drug interactions (DDI). The drug discovery process moves forward when a molecule is identified as a Lead. Lead molecules undergo profiling and metabolite identification to support drug discovery.
We present four case studies highlighting innovation in discovery and the regulated environment. These case studies exhibit the complexities associated with BIOA and elaborate on innovative solutions.
Case Study #1: Friendly Isotopes – allies to the metabolite ID scientist, use of stable labeled analogs can be used to assist in identification of biotransformation products. Case Study #2: Analysis of oligonucleotide therapeutics in biological matrices and investigation of biotransformation products. Case Study #3: Use of Neoteryx Mitra tips for whole blood sampling and subsequent use for developing qualified and validated methods. Case Study #4: Validation of a cortisol and cortisone assay using synthetic human urine calibration in the measurement of analyte levels significantly below average endogenous concentrations.
