DMPK Insights

In this podcast, Scott and John will discuss the LC-MS techniques that have been applied for the bioanalysis of biotherapeutics.

The episode explores the following:

• The impact that mass spectrometry is having in the biotherapeutics and biomarker space
• The rationale behind the use of LC-MS for certain biomarkers and how sensitive LC-MS assays can be developed (and the practical limits for lower limits of quantification that can be achieved)
• Developments in mass spectrometry that are expected to benefit the analysis of biomarkers and for biotherapeutics

Speaker:

John Mehl – Consultant 

John Mehl is currently consulting and previously worked as a director at GSK, leading the Protein MS group within the Bioanalysis, Immunogenicity and Biomarkers (BIB) department, Collegeville, PA. The group developed LC-MS assays for quantitative & qualitative analysis of biopharmaceuticals, protein & small molecule biomarkers and for the determination of in vivo protein turnover kinetics to support preclinical and clinical studies. Prior to joining GSK, John worked for BMS where he was a Sr. Principal Scientist focused on biomarker & large molecule quantification and characterization using MS.  John has a PhD degree in analytical chemistry from Vanderbilt University, postdoctoral training in protein MS from MIT and an MBA in business management from Temple University.  Before joining BMS, John worked for Merck in different analytical research areas including proteomics, small molecule DMPK, large molecule immunoassay method development and vaccine and biologics protein characterization, spanning both discovery and regulated laboratories.  He has published extensively on the use of hybrid LC-MS for both large and small molecule quantification.

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This podcast format is inspired by the Charles Dicken’s novella “A Christmas Carol” whereby Phil Jeffrey (Bicycle Therapeutics), Beth Williamson (UCB) and Daniel Price (Nimbus) discuss DMPK Past, Present and Future with Scott.  Key elements discussed include the evolution of DMPK as a predictive discipline that links helps the chemistry of drug design with the biology of drug disposition and effect.

The episode addresses the following questions:

• The founding names and principles of DMPK and the emergence of Discovery DMPK
• Today’s use of technologies and in silico modelling and DMPK’s role in the 3 pillars/5Rs and PK/PD 
• The outlook for better prediction with advances in AI/ML

Speakers:
Phil Jeffrey - Senior Vice President of Preclinical Development at Bicycle Therapeutics

Phil Jeffrey is now semi-retired after contributing to DMPK for over 35 years in the pharmaceutical industry.  Most recently, Phil was Senior Vice President of Preclinical Development at Bicycle Therapeutics and previously has held positions at Pfizer, GlaxoSmithKline, SmithKline Beecham and The Upjohn Company.  Phil is a longstanding contributor the Society for Medicines Research and is an Honorary Professor at the William Harvey Research Institute, Queen Mary University of London.  Phil has a wide breadth of experience across DMPK from, Drug Discovery and early lead optimisation through to clinical proof of mechanism and proof of concept across a wide variety therapeutic areas and drug modalities and made significant contributions to the advancement of understanding the CNS penetration of drugs into the brain.

Beth Williamson - Head of ADME in the DMPK group at UCB

Beth graduated with a PhD in Pharmacology from the University of Liverpool and is now Head of ADME in the DMPK group at UCB where she also represents DMPK on projects throughout discovery and development. Beth’s work has focussed on in vitro and in vivo ADME assay optimisation and validation within drug discovery, particularly to address bespoke questions. Beth has worked in the fields of oncology, neurology and immunology. Her main research interests include drug-drug interactions, extrapolation of pre-clinical in vitro and in vivo data for the prediction of human pharmacokinetics and application of AI/ML approaches within DMPK.  

Daniel Price - Vice President of Computational Chemistry & Structural Biology at Nimbus Therapeutics

Dr. Daniel Price is Vice President of Computational Chemistry & Structural Biology at Nimbus Therapeutics, where he leads a team of internal and external scientists focused on delivering breakthrough medicines through structure-based design, leveraging both physics-based and knowledge-based predictive modeling.  Before joining Nimbus, he spent 16 years at GlaxoSmithKline, where he led a team of computational chemists and data scientists across diverse areas of structure- and ligand-based drug design, high-content screening analytics, predictive ADME, predictive synthesis, and chemogenomics.  He has led drug discovery programs, contributed to 4 clinical candidates, led the development of GSK’s first generation R&D data lake, and authored/co-authored 26 publications.  Dr. Price received his undergraduate degree in chemical engineering from University of Colorado at Boulder followed by his Ph.D. in Molecular Biophysics & Biochemistry from Yale University with Prof. Bill Jorgensen.   He completed an NIH postdoctoral fellowship with Prof. Charlie Brooks, III at The Scripps Research Institute prior to joining GSK. 

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In this podcast, Josephine Bunch, Principal Research Scientist and Co-Director of the National Centre of Excellence in Mass Spectrometry (NiCE-MSI) at NPL,  talks about her work, and in particular her involvement in the Cancer Research UK Grand Challenge Programme.  

The episode explores the following:

• Recent innovations in MSI 
• Challenges associated with analyzing ever more complex molecules
• Label-free vs labelled imaging
• Hardware and software improvements and how these affect the industry
• Combining imaging techniques to extract maximum information
• Exciting developments for the future, including personalized medicine and the innovative technologies that will make this a reality

Speaker:
Josephine Bunch, Ph.D. - Principal Research Scientist and Co-Director of the National Centre of Excellence in Mass Spectrometry Imaging (NiCE-MSI) at NPL

Josephine completed a Ph.D. in mass spectrometry imaging at Sheffield Hallam University, followed by a post-doc appointment at the University of Sheffield. Josephine then led a research group at the University of Birmingham, where she also lectured in Chemistry and Imaging. Josephine is currently based at the National Physics Laboratory where she is Co-Director of the National Centre of Excellence in Mass Spectrometry Imaging (NiCE-MSI) and is also Chair of Biomolecular Mass Spectrometry at Imperial College London.  She is currently leading the Cancer Research UK Grand Challenge programme – a fascinating project that aims to deliver new insights into cancer and cancer treatments using the latest mass spectrometry imaging techniques. 

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In this podcast, Scott Summerfield, Senior Director, Pharmaceutical Metabolism at Pharmaron discusses his recent publication on Free Drug Theory (FDT) with Simon including the principles, arguments, and project impact. This article was an invited contribution to a special edition of the Pharmaceutical Research Journal recognizing the achievements of Professor Margareta Hammarlund-Udenaes and Kp,uu.

The episode addresses the following questions:

• What is the FDT?
• How FDT relates to fundamental physical and biochemical principles?
• How ambiguity in its definition can hamper discussions in drug design?
• Importance of linking drug-at-target concentrations to drug-target binding
• How to apply FDT as a starting point to understanding concentration-effect relationships and PK/PD?

Speaker:
Scott Summerfield, Ph.D.  - Senior Director, Pharmaceutical Metabolism at Pharmaron

Dr Scott Summerfield is currently Senior Director and Head of Pharmaceutical Metabolism at Pharmaron where he leads the UK group and its support of the Life Sciences industry.  He studied Chemistry at Coventry University followed by a PhD in Biological Mass Spectrometry at Warwick University and then a Post Doctoral fellowship at Manchester University.  Scott joined the Pharma industry in 1997 as a member of SmithKline Beecham’s DMPK group.  At the formation of GSK he moved to Neuroscience Discovery serving in a range of roles from leading the bioanalytical and biotransformation team, DMPK program representative, and member of the company’s Blood-Brain Barrier Working Group.  Scott has led WW groups supporting nonclinical and clinical PK and Biomarker Bioanalysis and has published over 60 scientific articles and book chapters.  He is a Fellow of the Royal Society of Chemistry, a children’s book author, a professional Coach, and a Kung Fu instructor.  

Reference:
Summerfield, S.G., Yates, J.W. and Fairman, D.A., 2022. Free Drug Theory–No Longer Just a Hypothesis?. Pharmaceutical Research, 39(2): 213-222. 

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In this podcast, Dan Weston, Scientific Leader, Biotransformation at GSK discusses his recent publication on the important role that Metabolite ID plays in drug discovery.

The episode addresses the following questions:

• Why studying biotransformation is an important part of early drug design 
• A strategy to combine in silico tools, high-resolution MS and software-assisted data analysis to optimize data delivery and quality
• How this influences medicinal chemistry and the design–make–test cycle

Speaker:
Dan Weston, Ph.D.  - Scientific Leader, Biotransformation at GSK

Dan gained his Ph.D. in ion-trap mass spectrometry from Nottingham Trent University.  He has held positions at Unilever (environmental fate using LC-MS); Schering-Plough (US) (small-molecule Met-ID for drug discovery); Nottingham Trent University (designing and building novel ion-mobility instrumentation); AstraZeneca (Met-ID for drug development); Waters (demo chemist, utility of ion mobility for small molecule applications); Sygnature (Met-ID Team Leader); and currently at GSK (Scientific Leader; providing cross-portfolio biotransformation support). His research interests include structural elucidation using novel mass spectrometric approaches; complementary analytical techniques such as ion mobility for data rationalization and insights into metabolite structure; in silico approaches for efficient data analysis; ambient ionization and rapid sample screening techniques

Reference:
Weston, D.J., Dave M., Colizza K. et al., 2022. A discovery biotransformation strategy: combining in silico tools with high-resolution mass spectrometry and software-assisted data analysis for high-throughput metabolism, Xenobiotica, 52(8): 928-942

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In this podcast, Dr. Paul Morgan, Head of DMPK at Grünenthal Group, discusses the development of the publication that introduced the “5R framework” and improved the likelihood of AstraZeneca candidate survival from candidate drug nomination to Phase III. We will then discuss how the area has developed since then and where the field may go in the future.

The episode addresses the following questions:

• What was the situation like that led to the development of the 5Rs?
• How was the analysis conducted?
• How was this analysis accepted both within the organization and externally?
• What changes occurred as a result of this?
• As we sit here today has this work led to the improvements suggested?
• What do you see as the future? Have we done enough? What else is needed?

Speaker:
Paul Morgan, Ph.D. - Head of DMPK at Grünenthal Group

Dr Paul Morgan has worked in Pharma R&D for 30 years across multiple therapeutic areas taking projects from early discovery through all stages of drug development and registration.  With specialism in Drug Metabolism and Pharmacokinetics (DMPK), he has led R&D departments in Pfizer, AstraZeneca, Sosei Heptares and now Grunenthal working across the interface between DMPK and Med Chem, Pharmacology, Safety, Clinical and CMC.  He has a keen interest in R&D productivity enhancement and has contributed to major initiatives at both Pfizer and AstraZeneca to introduce frameworks for the improvement of drug survival.   Paul is an honorary senior lecturer in Department of Pharmacology at University of Liverpool where he did his PhD.   

Paul is originally from Belfast, Northern Ireland and is currently based in North-West England just outside Manchester.  He is married with two grown-up children and a lively dog!

References:

1. Morgan, P., et al, 2018. Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nature reviews Drug discovery 17.3: 167-181.
2. Summerfield, S.G., Yates, J.W. and Fairman, D.A., 2022. Free Drug Theory–No Longer Just a Hypothesis?. Pharmaceutical Research, 39(2): 213-222. 
3. Smith, D.A., and Rowland, M., 2019. Intracellular and intraorgan concentrations of small molecule drugs: theory, uncertainties in infectious diseases and oncology, and promise. Drug Metabolism and Disposition 47.6: 665-672.
4. Smith, D.A., Di, L. and Kerns, E.H., 2010. "The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery." Nature reviews Drug discovery, 9.12: 929-939.

Stay tuned for more podcasts in our Pharmaron DMPK Insights Series!