DMPK Insights

For a captioned version or to access the transcript, please visit https://www.pharmaron.com/knowledge-center/dmpk-podcast-11-gut-microbiome/.

In this podcast, Chris Bode (Pharmaron US Labs) interviews Peter Turnbaugh, a microbiologist and Professor of Microbiology and Immunology at the University of California San Francisco. Over the past 15-20 years, Peter has produced so much groundbreaking research in the endlessly fascinating field of the gut microbiome. His work is not limited to DMPK by any means, but in this episode, we discuss drug metabolism by gut bacteria and its impact on pharmacokinetics. Clinically, reduced efficacy and/or increased side effects observed in some patients can be attributed to the gut microbiome, including narrow therapeutic index drugs such as digoxin. You will come away with an appreciation for scientific creativity and the sometimes unexpected benefits of doing an experiment that everyone thinks is going to fail. We speculate on how much there is to learn about the possible interactions between the gut microbiome and drugs for obesity, including GLP1 agonists. Finally, we talk about some practical considerations in terms of studying bacterial drug metabolism in vitro.  

 The episode explores the following: 

• How important is the gut microbiome in terms of drug metabolism? 
• What do we know about the balance between control of the microbiome by the host and control of the host by the microbiome? 
• What are some of the challenges of studying gut bacterial drug metabolism in vitro? 
• Could gut bacteria play a role in the efficacy and/or side effects of GLP1 agonists such as semaglutide, used to treat obesity and diabetes? 

Speaker:

Peter J. Turnbaugh – Professor, Department of Microbiology & Immunology at the University of California

Peter J. Turnbaugh, Ph.D., is a Professor in the Department of Microbiology & Immunology, the G.W. Hooper Research Foundation, and the Benioff Center for Microbiome Medicine at the University of California, San Francisco. He is also a CZ Biohub-San Francisco Investigator. For the past two decades, his research has focused on the metabolic activities of the trillions of microbes that colonize our adult bodies. Dr. Turnbaugh and his research group use interdisciplinary approaches in preclinical models and human cohorts to study how the gut microbiome influences nutrition and pharmacology. He received a B.A. in Biochemistry, Biophysics, and Molecular Biology from Whitman College and a Ph.D. in Microbial Genetics and Genomics from Washington University in Saint Louis. From 2010-2014 he was a Bauer Fellow in the FAS Center for Systems Biology at Harvard University, where he established an independent research group before starting his faculty position at the University of California, San Francisco. Notable honors include the Kipnis Award in Biomedical Sciences, the Needleman Pharmacology Prize, the Damon Runyon-Rachleff Innovation Award, the Searle Scholars Award, the Burroughs Wellcome Fund Investigators in the Pathogenesis of Disease Award, and fellowship in the American Academy of Microbiology.

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In this podcast Simon Taylor (Pharmaron UK) interviews Kevin Beaumont, a highly experienced DMPK scientist, leader and drug developer who has lived and breathed the role of the DMPK Project Representative throughout his 40-year industrial career.  With experience of delivering clinical drug candidates across multiple therapeutic areas with two major pharma companies (Pfizer and AstraZeneca) Kevin describes his entry into the role, the value of people, in roles as mentee and mentor, and the shift in emphasis of DMPK from a discipline supporting drug development to one driving drug discovery.  Covering key concepts related to project DMPK and minimising drug attrition this is a wide-ranging discussion with real life examples spanning discovery to clinical. 

The episode explores the following: 

• The key role of the DMPK Project Representative and required knowledge 
• Important concepts that have shaped DMPK drug design such as 
  • Physicochemical and application to drug design 
  • Free drug theory 
  • Human PK prediction, value and uncertainties 
  • Modalities  
• The role of DMPK in reducing drug failure in the clinic  
• Key individuals that have shaped DMPK science and Kevin’s career 
• The future of the DMPK Project Representative and the next generation  

Speaker:

Kevin Beaumont – Senior Director DMPK, Oncology R&D, AstraZeneca 

Kevin has worked in the pharmaceutical industry for over 40 years in the fields of drug metabolism and pharmacokinetics, especially as it relates to drug discovery support. His major area of expertise is in the modulation of physicochemistry to affect drug disposition and in prediction of human pharmacokinetics from preclinical information. He is the author of over 50 peer reviewed publications.  

Kevin joined the Department of Drug Metabolism at Pfizer Sandwich UK in 1983, directly from his BSC in Biochemistry at the University of London.  Under the mentorship of Dr Dennis Smith Kevin’s early career involved developing a fundamental understanding of the basics of DMPK support to discovery and development projects. This included developing expertise in small molecule bioanalysis, completion of radiolabelled ADME studies and direct DMPK support to discovery and development projects.  

In 2011, Kevin transferred to Pfizer Inc in Boston Massachusetts, where he was responsible for DMPK/ADME support to the Cardiovascular, Inflammation and Immunology and Rare Disease Therapeutic Areas.  

In 2020 Kevin returned to the UK and is currently with AstraZeneca supporting Oncology R&D with DMPK expertise including modalities beyond small molecules. 

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In this podcast, listeners will join us in celebrating the remarkable career of Professor Amin Rostami, a trailblazer in the realms of PBPK and QSP. Following his 60th birthday, Professor Rostami will provide insights into his journey, the dynamic evolution of PBPK and QSP, and the exciting horizons ahead. Tune in for a deep dive into the intersections of academia and industry, technological advancements, and the invaluable lessons garnered throughout a pioneering career.

The episode explores the following:

• The key milestones and highlights of Professor Amin's career in PBPK and QSP
• The factors that initially captivated his interest in PBPK, and how the field evolved over the decades of his career
• The role of translational and systems pharmacology in shaping the future of drug development
• Balancing between academic and industry roles
• Advice to young scientists and researchers entering the field of PBPK

Speaker:

Amin Rostami-Hodjegan, PhD, FCP, FAAPS, FJSSX, FBPS – Professor of Systems Pharmacology & Director of Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester, UK. SVP of R&D, Chief Scientific Officer (CSO), Certara, Princeton, USA
The work of Professor Rostami covers wide areas of drug development over the last 30 years, ranging from pharmaceutics (e.g. bioavailability and bioequivalence) to clinical pharmacology (e.g. mixture pharmacology of drug/metabolites), translational and systems pharmacology (e.g. quantitative proteomics of enzymes and transporter for in vitro to in vivo (IVIVE) scaling). As the Director of Centre for Applied Pharmacokinetic Research (CAPKR) at the University of Manchester, Amin collaborates with many pharmaceutical companies with a view to transfer latest scientific applications into modern drug development.  Amin was co-founder of two spin-off companies from the University of Sheffield (Simcyp Limited [now part of Certara Inc]) and Diurnal Limited [now part of Neurocrine Bioscience]). As a leader in the field of Physiologically-based Pharmacokinetics (PBPK) and Quantitative Systems Pharmacology (QSP), he is internationally recognized for his expertise in IVIVE to predict the behavior of drugs in human body and understanding the associated inter-individual variabilities. He was one of the founding editors of Pharmacometrics and System Pharmacology and serves on the Editorial Boards of several other journals. As the Senior Vice President of Research & Development (SVP) and Chief Scientific Officer at Certara, he facilitates the incorporation and integration of the latest advances in translational modelling to bio-simulation platforms offered by Certara to its clients, with the aim of accelerating the development and regulatory approval of safer drug products and bringing them to the patients. 

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In this podcast, Robert MacNeill, Professor Michael Bartlett of the University of Georgia and Dr. Guilherme Guimaraes of Biogen, will focus on oligonucleotide LC-MS covering the exciting key challenges, the pivotal nature of sensitivity in such assays, and the various analytical approaches and technologies that have been used, currently in use or being developed. 

The episode explores the following:

• How recent liquid chromatographic and mass spectral innovations have impacted the bioanalysis of these drug modalities
• Where innovation is taking us particularly in terms of the increasing profile of high-resolution mass spectrometry and the push toward chromatographic miniaturization

Speakers:

Michael G. Bartlett, Ph.D., FAAPS – University Professor, Associate Dean for Science Education, Research and Technology, College of Pharmacy, University of Georgia  – Professor, Department of Metabolism, Digestion and Reproduction at Imperial College
Over the past 29 years at the University of Georgia, Dr. Bartlett's group has been involved in the development, validation and implementation of novel bioanalytical methodologies to advance biomedical research.  His laboratory works broadly in the areas of drug discovery, development and toxicology resulting in over 190 peer-reviewed publications in a wide variety of areas.  His research has been supported by the NIH, EPA, DOD, ACS and industry.   

One area where Dr. Bartlett's lab has gained particular notoriety is in the use of LC-MS to analyze oligonucleotides. This work began during his time at the University of Utah but has accelerated over the past 15 years. Dr. Bartlett's group has studied many aspects involved in the use of LC-MS to evaluate therapeutic oligonucleotides for quality control, bioanalysis, pharmacokinetics and metabolism. They have also adapted many of these approaches to analyze microRNAs as potential disease biomarkers.  Finally, they have actively worked with many companies on the use of LC-MS to determine oligonucleotides including Pfizer, Ionis, ProQR, Newomics and Waters.   

Guilherme Guimaraes – Scientist DMPK at Biogen
Dr. Guilherme (Gui) Guimaraes is a scientist in drug metabolism and pharmacokinetics at Biogen. He is responsible for bioanalytical analysis of small molecules and antisense oligonucleotides.  Gui holds a Ph.D in pharmaceutical and biomedical sciences and a masters in international biomedical regulatory sciences from the University of Georgia. His graduate work was focused on the application of novel analytical strategies to improve the chromatographic performance and sensitivity of oligonucleotide LC-MS methods. Some of these strategies include the use of low adsorption surfaces and HILIC microflow LC – nanoelectrospray MS.  

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In this podcast, Professor Ian Wilson, a globally recognised and leading expert in drug metabolism, with over 500 publications in the field, takes us on an engaging journey exploring the link between carboxylic acid containing drugs and their involvement in DILI. A special focus will be given to Ian’s latest paper: ‘Minimizing the DILI potential of carboxylic acid-containing drugs: a perspective’.

The episode explores the following:

• Are acyl glucuronides shouldering too much of the blame?
• Where else should we be looking?
• What are the possible risk mitigation strategies to reduce DILI with these chemotypes?

Speaker:

Ian Wilson – Professor, Department of Metabolism, Digestion and Reproduction at Imperial College
Ian Wilson trained as a biochemist at the University of Manchester Institute of Science and Technology UMIST) following this with a PhD in the Chemistry Dept. at Keele University on the gas chromatographic analysis of ecdysteroids (insect moulting hormones). Following a short period of postdoctoral research on HPLC-based methods for the analysis of penicillamine at University College in London he joined Pharma were he the embarked on a career in drug metabolism and bioanalysis is the pharmaceutical industry spanning over 30 years (beginning in 1979 at Hoechst, the ICI, Zeneca and AstraZeneca). On leaving AstraZeneca he joined Imperial College (London) in 2012 where he is currently a Visiting Professor of Drug Metabolism and Molecular Toxicology. More recently he has also been appointed as a visiting Prof at Liverpool University. As a biochemist turned analytical chemist, he tries to use advanced analytical methods, including those based on UHPLC and ion mobility separations to better characterize and understand biological systems. Currently these efforts are focused on high resolution, high throughput methods that can be applied to problems in metabolic phenotyping (metabonomics/metabolomics), drug metabolism/biochemical toxicology, systems biology and the microbiome. He is the author, or co-author, of over 600 papers, reviews or book chapters, and has received awards in separation and analytical science from the Royal Society of Chemistry and the Chromatographic Society amongst others.  

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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.

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