ADME Strategies: Navigating a Path from Discovery Through Nonclinical and Clinical Development

Attendees in lecture hall at ADME Strategies: Navigating a Path from Discovery Through Nonclinical and Clinical Development

Investigation of the ADME properties of potential therapeutic agents is a key feature of both drug discovery and nonclinical/clinical drug development programs. In these presentations, we will explore different testing strategies which support these areas. We will review the current regulatory requirements for the conduct of ADME studies, discuss the relevance and importance of radiolabelled ADME studies in the development of novel drugs and review the application of qualitative mass spectrometry techniques in ADME programs.

DMPK strategies in Integrated Drug Discovery
Presented by: Dr Mike Briggs, PhD | Scientific Director, DMPK, Charles River

Successful Lead Optimisation employs integrated drug metabolism and pharmacokinetic (DMPK) strategies to drive drug discovery projects and identify preclinical proof of concept compounds and candidate molecules with excellent developability profiles.

Compounds with good functional activity are evaluated in in vitro and in vivo DMPK studies to provide information on in vitro/in vivo correlations; understanding of liabilities; and the design and interpretation of PK/PD studies to demonstrate target engagement. The use of these assays early in the screening cascade is pivotal to the identification and selection of potent and bioavailable compounds and enables preliminary human dose prediction.

 

Do Radiolabelled Mass Balance and Distribution Studies Still Have a Role to Play in the Development of Small Molecule Therapeutics?
Presented by: Stephen Madden, BSc PhD CBiol FRSB | Head, Regulatory ADME and Discovery Sciences, Charles River

In this presentation, we will review the use of radiolabelled non-clinical in vivo studies to investigate the ADME properties of small molecule therapeutic agents. We will discuss the design of such studies, the timing of the studies in relation to the pre-clinical and clinical compound development program and review the value that the data generated from these studies can bring to the safety package.

 

Metabolite Identification with Challenging Matrices in Regulatory Development
Presented by: James O’Neill, MChem, PhD | Scientific Manager, High Resolution Mass Spectrometry, Charles River

The rapid and robust identification of metabolites in complex matrices resulting from regulatory studies is an ongoing challenge in new product development. The application of high resolution LC-MS and LC-MS/MS remains the primary tool in industry for this purpose. Whilst developments in instrument sensitivity, resolution and dynamic range are welcome, this does not negate the importance of a good quality sample, especially with the associated cost of state of the art LC-MS instrumentation and the time pressures which exist in regulatory development. This presentation will highlight some of the useful techniques the analytical chemist should have in their tool box to deploy for the clean-up of awkward samples and some creative chromatographic, spectrometric and software solutions which can rapidly accelerate identification of metabolite structures.

‘Wet chemistry’ techniques including the use of solid phase extraction, compound derivatisation, chemical extraction and approaches to bound residues shall be discussed. From an instrument standpoint, the benefits of two dimensional approaches to sample chromatography shall be discussed, including employing orthogonal mixed mode and size exclusion column chemistries. Lastly, the application of metabolism software with product ion maps and the use of travelling wave ion mobility mass spectrometry will be touched upon which permit the user to mine additional information from a single injection of precious sample.

 

In-Vitro Drug-Drug Interactions; Guidances and Assays
Presented by: Mira Wenker, PhD, ERT | Section Head Drug Metabolism and Pharmacokinetics, Charles River

Drug-drug interactions are a key event in the development and safety assessment of pharmaceuticals. Both the FDA and EMA have guidelines advising on the conduct of in-vitro studies to evaluate the potential for drug-drug interactions. In October 2017, the US FDA revised and split its 2012 draft guidance for industry on in vitro drug-drug interaction (DDI) studies, into one document for in vitro DDI studies and another for clinical DDI studies. This presentation will offer perspectives on major changes in the in vitro guidance, how it affects the conduct of the in vitro studies and what the implications are for the in vitro testing strategy.

Dr Mike Briggs, PhD | Scientific Director, DMPK, Charles River
DMPK strategies in Integrated Drug Discovery

Mike Briggs headshot.Mike is a drug metabolism and pharmacokinetics expert with 25 years of experience gained in small and large pharma and CRO industry. During this time, Mike delivered the integrated DMPK package for 20 candidate molecules through strategic and scientific DMPK leadership. Mike joined our Discovery organisation 7 years ago, and provides DMPK guidance across our discovery portfolio.

Prior to joining CRL, Mike worked in neurosciences (GSK) and pioneered integration of PK/PD to drive candidate selection. Mike has worked on the delivery of candidate molecules in respiratory, pain, neurological, oncology, metabolic and gastro-intestinal disease areas, and project led four discovery programmes to development candidate selection.


Stephen Madden, BSc PhD CBiol FRSB | Head, Regulatory ADME and Discovery Sciences, Charles River
Do Radiolabelled Mass Balance and Distribution Studies Still Have a Role to Play in the Development of Small Molecule Therapeutics?

Stephen Madden headshot.Steve is currently Head, Regulatory ADME and Discovery Sciences, having previously been Head, In Vitro Sciences (appointed to this role in February 2006) at Charles River Edinburgh. He is Chair of the Animal Welfare and Ethics Committee at the Edinburgh site and he regularly represents Charles River in meetings with external groups and agencies such as NC3Rs, Scottish Life Sciences Association, Skills Development Scotland and various Universities, Colleges and Schools. Steve is a previous Committee Member of the Drug Metabolism Discussion Group, acting as Secretary from September 2003-September 2005 and as Chair from September 2005-September 2006. Steve holds a BSc in Biochemistry from the Glasgow University and a PhD in Pharmacology from Liverpool University.


James O’Neill, MChem, PhD | Scientific Manager, High Resolution Mass Spectrometry
Metabolite Identification with Challenging Matrices in Regulatory Development

James O’Neill headshot.James O’Neill earned his Masters in Chemistry in 2008 and PhD in Chemistry in 2012 from Heriot Watt University, Edinburgh. In 2007, James spent a summer internship with Charles River where he was first introduced to Agrochemical and Pharmaceutical Safety Assessment. In 2012, James returned to Charles River Edinburgh, where he accepted a graduate position in the Chemistry department, specialising in the application of high resolution mass spectrometry to metabolite structure elucidation. Since then he has worked closely with a number of leading agrochemical and pharmaceutical companies as they look to out-source their analytical needs to help bring their products to market. Since 2017, James has overseen the high resolution mass spectrometry team at the Edinburgh site.


Mira Wenker, PhD, ERT | Section Head Drug Metabolism and Pharmacokinetics, Charles River
In-Vitro Drug-Drug Interactions; Guidances and Assays

Mira Wenker headshot.Mira is currently working at Charles River, The Netherlands, where she is Head of the Drug Metabolism and Pharmacokinetics group. She is leading a team of Study Directors that are involved in designing, performing and reporting in-vitro ADME assays, in-vivo ADME and PK studies and TK evaluations. While these are mainly done for the Pharmaceutical Industry, the area of DMPK is becoming more and more important for Agrochemical and Chemical products, making this a very broad and challenging area. Prior to her current position, she worked as Head of in vivo ADME, PK and TK at what was then WIL Research. She started her career as Study Director for in vivo ADME, PK and TK evaluations at NOTOX B.V.

She has a PhD in BioMedical Sciences from the University of Amsterdam where she worked on interindividual variability in metabolism of organic solvents in relation to occupational toxicology. Previously, she obtained a MSc in human nutrition and toxicology. She is recognized as a Board certified Toxicologist by the Dutch Society of Toxicology since 2002, and is a registered European Toxicologist (ERT). She is a tutor on pharmacokinetics courses and has published and presented over the years on the field of drug-drug interactions, metabolism, (skin) absorption, microsampling and kinetics.