ISSX Newsletter | Issue 1, 2023

ISSX President’s Message

By Scott Obach, ISSX President

Greetings Fellow ISSX Members!

I have just returned to the US after participating in the Asia-Pacific ISSX Conference that was in Bengaluru, India. What a fantastic meeting and fantastic experience!! The presentations were some of the best I’ve heard in a long time; perhaps we all had a lot of pent-up science from three years of pandemic isolation. Congratulations to Thanga Mariappan and his team for organizing such an engaging meeting. I’m sure that there will be summary of the meeting highlights in an upcoming issue of the ISSX Newsletter. And congratulations to Hiroshi Yamazaki for receiving a well-deserved ISSX Asia-Pacific Achievement Award which he received at the meeting for his sustained and prolific output of research on P450 enzymes and other topics. It was encouraging to see the energy and interest from so many young attendees participating in the meeting—this portends the

future success of India in xenobiotic research. And finally, as I had mentioned in a previous letter, I had an intent to experience a Bollywood movie in an Indian theater, and that intent was fulfilled with six of us seeing Pathaan on Tuesday night after the conference. Three hours of over-the-top thrills, stunts, violence, and action, and, of course the expected interludes of music and dance included in Bollywood films. Wow!

Very soon we’ll have our first virtual workshop of 2023 and the topic is one that particularly excites me— Drug Metabolites. This will run March 1–3 for four hours each day. Check out the Workshop Program , and join me online in March. Presenters will be from drug metabolism labs of pharmaceutical companies, government scientists from regulatory authorities, and academic researchers. Remember to register; this is not one to miss. I can’t wait!

With the AsiaPacific regional meeting behind us, we can turn our attention to our other two regional conferences in 2023. First will be the European ISSX Meeting at the University of Hertfordshire, in the United Kingdom, just a short trip from London June 11–14. The meeting is combined with the DMDG so the conference will contain elements from both meetings. Later in the year, we’ll host the 25 North American ISSX Meeting in Boston. Programs for both are finalizing so keep your eyes open on the ISSX Website for these, and I look forward to seeing everyone’s interesting lab findings in the poster sessions.

Scott Obach ISSX President

Changes on the ISSX Council

As the New Year begins, we welcome the newest Council members, Hiroshi Yamazaki and Swati Nagar to the ISSX Council. We also welcome back Simone Schadt to the ISSX Council.

Hiroshi, Swati, and Simone began their two-year terms of service on Council on January 1, 2023. Hiroshi represents the Asia Pacific region, and Swati represents the North American region. Simone continues to represent the European region.

HIROSHI YAMAZAKI has been Professor of the Laboratory of Drug Metabolism and Pharmacokinetics at Showa Pharmaceutical University, Tokyo, Japan since 2005. After receiving his B.S. and M.S. degrees from Gifu Pharmaceutical University and a Ph.D. in Pharmaceutical Sciences from Osaka University in Japan, he trained as a post-doctoral fellow at Vanderbilt University School of Medicine, Nashville, TN, USA in 1994. He was recruited as an Associate Professor at Kanazawa University from Osaka Prefectural Institute of Public Health and then an Associate Professor at Hokkaido University Graduate School of Pharmaceutical Sciences in 2001. Professor Yamazaki’s research has focused on cytochromes P450, flavin-containing monooxygenases, and simple pharmacokinetic modeling. His P450 papers cover a broad range of topics. He has authored over 520 original publications ( http://orcid.org/0000-0002-10684261 ) with an h-index of 66 in Scopus (Author ID: 557193405959 ).

Professor Yamazaki is a member of several professional societies and editorial committees. He is a recipient of the Japanese Society for the Study of Xenobiotics (JSSX) Award and Fellowship, and was ex-JSSX President (2017-19) and Editor-in-Chief of Drug Metabolism and Pharmacokinetics (2014-17), which has recently been publishing ISSX meeting abstracts.

SWATI NAGAR is a Professor in the Department of Pharmaceutical Sciences at Temple University School of Pharmacy. She obtained her Ph.D. in Pharmaceutics at the University of Minnesota in 2003. She completed a postdoctoral fellowship in Pharmacology at Fox Chase Cancer Center in 2005. Swati joined Temple University School of Pharmacy, Department of Pharmaceutical Sciences in 2005 as Assistant Professor, and was promoted to the rank of Associate Professor with tenure in 2011, and Professor in 2018. She teaches PharmD and graduate pharmacokinetics.

Swati’s lab has a long-standing interest in understanding the disposition of conjugated metabolites, specifically the pharmacokinetics of metabolites with respect to their formation and transport. Further, in collaboration with Dr. Ken Korzekwa, she is developing methods to better understand complex kinetics of time-dependent inhibition. Another key collaborative area of research with the Korzekwa lab is developing models to predict intracellular concentrations in the presence of drug transporters.

Swati has co-authored several peer-reviewed research and review articles, and she co-edited a book titled ‘Enzyme Kinetics in Drug Metabolism: Fundamentals and Applications’ (Springer/Humana Press; 1st edition 2014; 2nd edition 2021). Swati is a past Chair of the

Changes on the ISSX Council

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Delaware Valley Drug Metabolism Discussion Group, a past Chair of the AAPS PPDM Drug Metabolism Focus Group, Chair of the 2018 Gordon Research Conference on Drug Metabolism, past member of the steering committee of the International Transporter Consortium, and a member of several professional organizations including ISSX. She currently serves on the editorial board of Drug Metabolism and Disposition and Xenobiotica.

SIMONE SCHADT is leading the ADME team at Roche (Basel, Switzerland). This team provides ADME support throughout drug discovery and development, ranging from small molecules and oligonucleotides to therapeutic proteins.

Simone has co-authored numerous publications on the effects and the fate of xenobiotics: reactive metabolite assessment and drug induced liver injury (DILI), metabolites in safety testing (MIST), tissue imaging and bridging DMPK and safety, oligonucleotide and protein biotransformation. Simone is a biochemist by training, with a major in immunology and organic chemistry, from the University of Tübingen (Germany). In 2007, she graduated with a Ph.D. in biochemistry and analytical chemistry from Technical University of Berlin (Germany) with a thesis on the mode of action of a novel antibiotic. After graduating, she started her industry career as a postdoctoral fellow at Boehringer Ingelheim in Biberach (Germany) in the field

of reactive metabolites and drug induced liver injury. She then took over a role as lab head in the drug metabolism group at Boehringer Ingelheim. In 2011, she joined the drug metabolism group at Roche. Simone is a diplomate of the American Board of Toxicology, a European Registered Toxicologist, and a current member of the ISSX Council.

ISSX also wishes to extend our thanks and appreciation for the work of our outgoing Council members, Kouichi Yoshinari and Jashvant (Jash) Unadkat.

Jashvant (Jash) Unadkat completed his second term on the ISSX Council. Jash has been instrumental to the governance of the Society of many ways, including serving as the co-organizer for the 2018 ISSX Workshop, and co-organizing the 21st North American Meeting. While serving on Council, Jash served as webinar moderators and presented his own research to ISSX members.

Kouichi Yoshinari finished his term on the ISSX Council at the end of 2022. While serving on the Council, Kouichi concurrently served on the Meeting Organizing Committee for the 12th International ISSX Meeting and served on the Finance Committee. Kouichi has also been instrumental in continuing ISSX’s relationship with JSSX, maintaining a strong relationship with both organizations. We are grateful to Kouichi for all of his contributions.

ISSX is grateful to both Jash and Kouichi for their service and commitment to ISSX.

Book Review

BIOCHEMISTRY OF DRUG METABOLISING ENZYMES: TRENDS

AND CHALLENGES.

Editors; MSH Akash, K Rehman Academic Press, Elsevier Science 2022

586pp. ISBN 978-0-323-95120-3

This book details the role of drug-metabolizing enzymes in the biotransformation of drugs and other xenobiotics, their regulation and factors affecting function, the influence of and activity within various disease states, and the use of technological procedures and computerised systems for measurement, prediction of metabolic activity and metabolites produced. The microflora and microfauna dwelling within the human gastrointestinal tract are addressed, detailing how microbially-mediated metabolism, especially via the processes of hydrolysis and reduction, may influence the pharmacokinetic and clinical outcome of an orally administered compound. It is pleasing to witness the explosion of research into this collection of bacteria, archaea, viruses, and fungi which comprise the human microbiome and the realisation of their vast importance; a vindication of the early work of such scientists as Ilya Metchnikov (1846-1916), Theodor Escherich (1851–1911), Henry Tissier (1866–1926), and Alfred Nissle (1874–1965) (see: Farré-Maduell, Casals-Pascual. Human Microbiome Journal 2019, 14, 100065). Pharmacogenetic aspects are described, especially amongst the cytochrome P450 enzyme family, and not forgetting the transporter proteins. The debacle of imprecise correlation between genotype and phenotype is mentioned and potential solutions are suggested. It is the clinical outcome which is paramount and the quest for prediction and acquisition of personalized medicine, the holy grail, is emphasized.

Eighty-five contributors have come together to provide twenty-two chapters, the titles of which are as follows. “Biochemical activation and functions of drug metabolizing enzymes,” “Computational approaches for drug-metabolising enzymes: Concepts and challenges,” “Role of drug-metabolising enzymes in biotransformation of drugs,” “Emerging environmental contaminants and drug-metabolizing enzymes,” “Drug-metabolizing enzymes and the fate of prodrugs: From function to regulation,” “Hormones and drug-metabolizing enzymes: From function to regulation,” “Receptors and drugmetabolizing enzymes: From function to regulation,” “Biochemistry of cathepsins enzymes and their

metabolic activity in the lysosome,” “Fate of drugmetabolizing enzymes in metabolic diseases,” “Fate of drug-metabolising enzymes in cardiovascular diseases: Concepts and challenges,” “Fate of drug-metabolizing enzymes in neurological diseases: Challenges and strategies,” “Impact of physiological factors on drugmetabolizing enzymes: From function to regulation,” “Xenobiotic and drug-metabolising enzymes: Challenges and strategies,” “Drug-metabolising enzymes and inflammatory response,” “Polymorphisms in drug metabolising enzymes: Challenges and strategies,” “Modulation of human microbiome and drug metabolism,” “Bioanalytical techniques for prediction of metabolic activity of drug-metabolising enzymes,” “Role of pharmacogenomics for prediction of personalized medicines,” “Dietary sources of drug-metabolizing enzymes: From production to regulation,” “Vitamin deficiencies and drug-metabolizing enzymes: Challenges and strategies,” “Fate of drug-metabolising enzymes in malnutrition: Challenges and strategies,” “Drugmetabolising enzymes and oxidative stress.”

This tome collects together and examines many important aspects of drug metabolism and the enzymes that bring about these biotransformations. It is a comprehensive work with a readership ranging from the student pursuing a career in the areas of biochemistry, pharmaceutical sciences, biotechnical research and drug development, to list but a few, through to the established worker who may need a reference book or delightful and thought-provoking reading material.

Notified by

Steve Mitchell

Imperial College London, UK

Book Ordering Information

Elsevier Inc. (S&T Books and Cell Press)

50 & 60 Hampshire Street, 5th Floor Cambridge, MA 02139, US

Elsevier Limited (Corporate Office)

125 London Wall

London EC2Y 5AS, UK

http://store.elsevier.com/Academic-Press

https://www.elsevier.com/books-and-journals

Small Molecule Metabolites in Drug Discovery and Development

March 1–3, 2023

INVITATION TO ATTEND

Please join us for an exciting virtual workshop, "Small Molecule Metabolites in Drug Discovery and Development," which has been organized through the efforts of the ISSX Biotransformation Mechanisms and Pathways Focus Group and is chaired by Carley Heck of Pfizer and Valerie Kramlinger of Vanderbilt University.

ABOUT THE WORKSHOP

This virtual workshop will focus on the impact of small organic molecule metabolism science on both drug discovery and drug development. This three day workshop will dissect the types of in vitro and in vivo drug metabolism studies conducted to support the drug discovery-development pipeline, including the experimental and analytical techniques used and the impact of the data generated. Some of the exciting topics to be covered are: the importance of drug metabolites, analytical techniques of metabolite ID, prediction of human circulating metabolite profiles, metabolite biosynthesis, human ADME study strategies and impact, and both the pharmaceutical industry and regulatory perspectives on the value of human ADME studies and drug metabolism science. Each session of this workshop will feature 4-5 expert speakers, a daily panel discussion, and poster sessions; the latter will be selected from the pool of abstracts from the students and industry attendees.

The workshop includes access to all presentation slides and recordings.

WORKSHOP ORGANIZERS

Workshop Organizing Committee Chairs: Carley Heck, Pfizer and Valerie Kramlinger, Vanderbilt University

Workshop Organizing Committee Members:

Matthew Albertolle, Takeda Pharmaceuticals

Bingming Chen, Merck & Co.

Wenkui Li, Novartis

R. Scott Obach, Pfizer

Simone Schadt, F. Hoffmann-La Roche, Ltd.

Faye Vazvaei-Smith, Merck & Co.

Douglas Spracklin, Pfizer

Aaron Teitelbaum, Boehringer Ingelheim

Rheem Totah, University of Washington

WORKSHOP REGISTRATION FEES

Registration Fees

ISSX Member $495

Nonmember $615

Student/Postdoc Member $99

Register today!

WORKSHOP PROGRAM*

Wednesday, March 1, 2023 | 10:00 am–3:30 pm ET (US)

Session 1

10:00 am–10:05 am | Welcome and Introduction

10:05 am–10:45 am | Why Drug Metabolites Can be Important; Examples of Active and Toxic Metabolites

Rheem Totah, University of Washington

10:45 am–11:30 am | Implementation of Innovative HRMS Instrumentation Strategies to Help Accelerate Metabolite Identification and Preclinical Drug Discovery

Mark Cancilla, Merck

11:30 am–11:45 am | Break

11:45 am–12:30 pm | Modern Method of Metabolite ID: Part 2. 1D and 2D NMR

Gregory Walker, Pfizer

12:30 pm–1:15 pm | Predicting Human Metabolites from Pre-clinical Information and Models – Qualitative and Quantitative

Ernesto Walker, Pfizer

1:15 pm–2:00 pm | Accessing Metabolites of Various Types – Biosynthesis, Isolation Methods

Elizabeth Gillam, University of Queensland

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Small Molecule Metabolites in Drug Discovery and Development

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2:00 pm–2:30 pm | Break

2:30 pm–3:30 pm | Panel Discussion

Thursday, March 2, 2023 | 10:00 am–3:30 pm ET (US)

Session 2

10:00 am–10:05 am | Welcome and Introduction

10:05 am–10:45 am | The Human ADME Study— Comparison of Various Strategies and Technical Approaches

Chandra Prakash, Agios

10:45 am–11:30 am | Accelerator Mass Spectrometry for the Support of Microtracer Studies @ BoehringerIngelheim, Technical Aspects of AMS' Deep Dive on How AMS Actually Works

Stefan Blech and Ralf Laux, Boehringer-Ingelheim

11:30 am–11:45 am | Break

11:45 am–12:30 pm | How to Deal with Metabolites from Human ADME: Part 1. MIST

Yuexia Liang, Merck

12:30 pm–1:15 pm | How to Deal with Metabolites from Human ADME: Part 2. Target Activity, DDI, and Modelling Impact Relative to Parent Drug

Sheila Peters, Boehringer Ingelheim

1:15 pm–2:00 pm | Panel Discussion

2:00 pm–2:30 pm | Break

2:30 pm–3:30 pm | Posters

Friday, March 3, 2023 | 10:00 am–3:30 pm ET (US)

Session 3

10:00 am–10:05 am | Welcome and Introduction

10:05 am–10:45 am | Industry Perspective on the Value of ADME Studies and Drug Metabolites

Douglas Spracklin, Pfizer

10:45 am–11:30 am | Drug Metabolites and Their Roles in Drug-drug Interactions

Xinning Yang, US FDA

11:30 am–11:45 am | Break

11:45 am–12:30 pm | Vignette 1

Simone Schadt and Kenichi Umehara, Roche

12:30 pm–1:15 pm | Vignette 2

Sekhar Surapaneni, BMS

1:15 pm–2:00 pm | Panel Discussion

2:00 pm–2:30 pm | Break

2:30 pm–3:30 pm | Posters

*Program subject to change.

Renew Your ISSX Membership for 2023

Thank you for your membership and support of ISSX!

If you haven’t yet renewed, we urge you to remain a part of the premier international association that advances research and education on the interplay of living systems with medicines and chemicals for the benefit of society worldwide by renewing your ISSX membership today.

The ISSX Webinar Series is one of our most popular benefits of membership and provides members with the opportunity to learn about a variety of topics presented by leaders in the field. The ISSX Focus Groups provide an excellent forum for scientific discourse and members are encouraged to join one or all four groups. In addition, the New Investigators Group is very active and this group provides an excellent way to connect with fellow early career scientists to share experiences and tips. Another point of connection for members is the ISSX Mentorship Program , which links early career scientists with experienced colleagues to provide career advice and discuss career options. Finally, ISSX members benefit from steep discounts to our highlyrated scientific meetings where they learn about the latest research developments, network with leaders in the field, and present their research in multiple forums. Please make plans to join ISSX in person at the ISSX/ DMDG 2023 Meeting at the University of Hertfordshire in the United Kingdom this June 11–14 and 25th North American ISSX Meeting in Boston, Massachusetts, USA from September 10–13.

MARK YOUR CALENDAR FOR THESE UPCOMING EVENTS

2023 will be an exciting year to expand your connections. We look forward to greeting you at our virtual and in-person educational events. ISSX members enjoy steeply discounted registration for workshops and meetings. Please save the dates and make plans to join us!

• March 1-3: The ISSX Transporters Focus Group is also organizing a virtual workshop, Small Molecule Metabolites in Drug Discovery and Development. Registration is now open and the program is available on the Workshop webpage!

• June 11-14 : ISSX is planning a joint meeting with the DMDG, which will be held in person at the University of Hertfordshire in the United Kingdom. View the program , submit your abstract , and register today!

• September 10-13: ISSX is hosting the 25th North American ISSX Meeting in Boston, Massachusetts, USA. Additional details will be announced in March!

Be sure to renew your membership to access the ISSX member discounts to attend!

Please follow the steps below to complete your renewal:

1. Visit issx.org/renew .

2. On the right-hand side of the page, log in with your ISSX username and password. If you do not know your username or password, you may re-set it by visiting issx.org/password

3. Click “RENEW YOUR MEMBERSHIP NOW” in the blue box at the top of your profile page.

4. On the next screen, review and update your contact information to ensure uninterrupted communication from ISSX.

5. Once you verify your contact information, you will be directed to the payment screen, where you may view your renewal options, including instant payment online via credit card.

• If you would like to pay by check, select "Bill Me" under Payment. You can access your invoice on the subsequent page and it will be automatically sent to you via email. Please print the invoice and submit it with your check to: ISSX 8652 Solution Center Chicago, IL 60677-8006

If you have questions about renewing your membership or membership benefits, please contact ISSX by phone at +1-202-367-1160 or by email at information@issx.org

Renew Your ISSX Membership for 2023

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DONATIONS

ISSX relies on assistance from members and other individuals as well as corporate entities to advance our mission. If you would like to make a gift to ISSX, please visit www.issx.org/donations to learn about the various funds you can support.

ISSX is a 501 (c)(3) organization incorporated in the United States. As such, your contribution may qualify for a tax deduction. Consult your tax advisor for full information. Our federal tax identification number is 22-2432063. If you need a copy of our federal W-9 form, simply email information@issx.org and we will promptly reply.

Meeting Chairs

Amit Kalgutkar, Pfizer and Fatemeh Akhlaghi, GBT

Meeting Organizing Committee

Scott Obach, Pfizer

Sandy Pang, University of Toronto

Amin Rostami, Certara

Jasleen Sodhi, Septerna

Dhaval Shah, University at Buffalo

Brooke Rock, Amgen

Yurong Lai, Gilead

Jose Manautou, University of Connecticut

Rheem A. Totah, University of Washington

Alison Betts, Applied Biomath

Deepak Dalvie, Crinetics Pharmaceuticals

Axel Paehler, Roche

Sharon Ripp, Pfizer

Program, Registration, and Abstract Submission details to be announced in March 2023! Watch for more information coming soon!

SAVE THE DATE: THE 25TH NORTH AMERICAN ISSX MEETING

The Westin Boston Seaport • Boston, Massachusetts, USA • September 10–13, 2023

The ISSX Webinar Series

ABOUT THE ISSX WEBINAR SERIES

The ISSX Webinar Series is an engaging and innovative way to hear from and interact with speakers from around the world on a range of topics related to the metabolism and disposition of xenobiotics. Members can participate for free. Participate in regularly scheduled live webinars with an exciting range of speakers, as well as watch previous webinars on your own schedule.

ISSX webinars are presented by internationally recognized scientists on a variety of subjects relevant to the field. The ISSX Continuing Education Committee is charged with the responsibility for reviewing these educational offerings and setting the webinar schedule.

MARK YOUR CALENDAR FOR THESE UPCOMING ISSX WEBINARS

MARCH 2023

March 14, 2023 at 10:00 AM ET US (15:00 UTC)

Albumin-Mediated Uptake of Highly Bound Anionic Drugs by Hepatic and Renal Transporters: A Real Phenomenon or an in vitro Artifact?

Presented by Dr. Mengyue (Melody) Yin, University of Washington, Seattle and Dr. Shawn Pei Feng Tan, University of Manchester, UK

Educational Needs Statement:

This webinar aims to highlight current knowledge about albumin-mediated uptake by organic anion transporters expressed in liver and kidney. Special emphasis will be placed on in vitro evidence to support the hypothesis and the complexity confounded by the non-specific binding of the drug-albumin complex. Possible implications to improve the prediction of transportermediated hepatic and renal clearance for highly protein bound drugs will be discussed.

Abstract:

Plasma proteins or human serum albumin have been reported to increase the in vitro uptake clearance of highly albumin-bound anionic drugs. Various hypothesis and mechanistic models have been proposed to explain such phenomenon. However, some controversial observations have suggested that possible artifact of the non-specific binding may complicate the data interpretation. This special webinar will be started with two presentations given by the graduate students (their works were presented at the 2022 North American ISSX meeting as poster presentations), followed by a panel discussion with all speakers, their scientific mentors,

and international renowned experts in the transporter field.The knowledge gained from this presentation will help scientists at all levels to learn the concept of albumin-mediated uptake effects by transporters; understand their complexity and current knowledge gaps. The discussion will also provide some insights and practical considerations on designing in vitro transport kinetic studies for highly protein bound drugs to improve their in vitro to in vivo extrapolation.

Questions:

If you would like to submit questions in advance of the session, please submit them to information@issx.org by Monday, March 13, 2023.

APRIL 2023

April 18, 2023 at 9:00 AM ET US (14:00 UTC)

Drug Metabolism and Pharmacokinetics (DMPK) in the Safe and Efficacious Use of Medicines in the Clinical Setting in Africa

Presented by Dr. Collen Masimirembwa, African Institute of Biomedical Science and Technology (AiBST) Zimbabwe

Questions:

If you would like to submit questions in advance of the session, please submit them to information@issx.org by Monday, April 17, 2023.

Educational Needs Statement:

This talk is meant to inform the global drug metabolism and pharmacokinetics research and applications community of DMPK work being done in Africa. It is hoped to highlight opportunities for research collaboration.

Abstract:

This talk is meant to inform the global drug metabolism and pharmacokinetics research and applications community of DMPK work being done in Africa. It is hoped to highlight opportunities for research collaboration. This webinar intends to focus on the following objectives:

1. Present progress in DMPK research and applications in Africa;

2. To demonstrate how preclinical and clinical DMPK has improved the use of drugs in the treatment of infectious diseases;

The ISSX Webinar Series

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3. To make the Global scientific community aware of the liver tissue biobank from people of African ancestry as a DMPK research resource they can access.

About the Speaker:

Prof. Collen Masimirembwa is the founding President and Chief Executive Officer of the African Institute of Biomedical Science and Technology (AiBST) in Zimbabwe. He is also a Distinguished Professor at the University of the Witwatersrand working at the Sydney Brenner Institute for Molecular Bioscience (SBIMB). Before that, he had worked as a Principal Scientist at AstraZeneca in Sweden in DMPK & Bioanalytics. Collen obtained his DPhil in Biochemistry at the University of Zimbabwe under the supervision of Prof. Julia Hasler and Ph.D. in Medical Biochemistry and Biophysics from the Karolinska Institute, Sweden under the supervision of Prof. Magnus Ingelman-Sunberg.

He is a leading researcher in pharmacogenetics and pharmacokinetics for drug discovery and development. His work focuses on the genomic diversity of pharmacogenes in African populations and its implications for the safe and efficacious treatment of infectious and non-communicable disease in people of African ancestry. He has developed the first registered clinical pharmacogenetic testing panel and dosing algorithm in Africa, GenoPharm, that is inclusive of genetic variations unique to Africans. In addition to collaborations among academic institutions, he strongly believes in collaborations with the pharmaceutical and biotech industry in order to translate research findings to life saving solutions. He promotes this research across Africa through collaborative research and has also initiated a successful MSc in Genomics and Precision Medicine program. To promote international collaboration in precision medicine, Collen is the Chair of the Developing World (South America, Africa & Middle East and South East Asia) Committee in the Pharmacogenomics Global Research Network (PGRN) and is a member of the Advisory Board of the Eu-Africa PerMed initiative. His work has won several awards including the Human Genome Organisations (HUGO) Award for Africa (2019) and the Bill and Melinda Gates Foundation (BMGF) Calestous Juma Science Leadership Award (2021) to expand clinical pharmacogenetic testing in Africa. Collen is a fellow of the Zimbabwe Academy of Sciences (ZAS) and of the African Academy of Sciences (AAS).

MAY 2023

May 23 2023 at 11:00 AM ET US (16:00 UTC)

Aldehyde Oxidase: What is Needed to Develop Robust Physiologically-Based Pharmacokinetic Models?

Dr. Sandhya Subash, Washington State University and Dr. Nihan Izat, University of Manchester, UK

Educational Needs Statement:

This webinar will highlight the challenges and limitations for prediction of in vivo clearance for aldehyde oxidase (AO) substrates in human. Further, the consequences of poor prediction of AO clearance when developing physiologically-based pharmacokinetic (PBPK) models for AO and dual AO-CYP substrates will be explained. Attendees will receive the latest research aimed at overcoming these challenges being performed by two academic centres of excellence.

Abstract:

This webinar will highlight the challenges and limitations for prediction of in vivo clearance for aldehyde oxidase (AO) substrates in human. Further, the consequences of poor prediction of AO clearance when developing physiologically-based pharmacokinetic (PBPK) models for AO and dual AO-CYP substrates will be explained. Attendees will receive the latest research aimed at overcoming these challenges being performed by two academic centres of excellence.

Joint webinar between Centre for Applied Pharmacokinetic Research (CAPKR; University of Manchester, UK) and Proteomics-based Research Initiative for Non-Cytochrome P450 Enzymes (PRINCE; Washington State University, US), two academic research consortia sponsored by pharmaceutical industry. Co-chairs: - Dr Daniel Scotcher (University of Manchester, UK) - Dr. Bhagwat Prasad (Washington State University, WA) Aldehyde oxidase (AO) is a cytosolic molybdoflavoprotein enzyme, expressed mainly in liver, with wide range of substrates and capable of mediating oxidation and reduction metabolism. Following from progress towards reducing cytochrome P450 (CYP) liabilities of new drugs, AO has emerged as an increasingly common alternative metabolic pathway for drug metabolism. In particular, several drug development programs have failed due to poor prediction of in vivo drug clearance by AO; for example, toxicity and poor bioavailability in first-in-human trials. This webinar will explain the existing challenges of

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ISSX President’s Message

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I have some updates about our efforts regarding increasing our organization’s presence in Africa. Zoë, Alex, and I have Zoomed monthly with a team of Rose Hayeshi, Makhotso Lekhooa, Julius Enoru, and Ogochukwu Amaeze, and are working to assemble a list of xenobiotic scientists from Africa to give a series of webinars on their research. The overall plan is to start with the webinar series and then develop a workshop on an area of xenobiotic science that has special relevance to Africa that would be held in Africa. The first webinar has been set up for April 18 and will feature Dr. Collen Masimirembwa of the African Institute of Biomedical Science and Technology in Zimbabwe. I look forward to robust participation from our entire constituency in support of our fellow scientists in Africa.

Finally, I would like to call upon a few volunteers to join me on a team to focus on our Learning Management System to make it a success that is useful for members. This team would be of a finite duration of a couple months, so it’s a great way to get involved

The ISSX Webinar Series

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in vitro-in vivo extrapolation (IVIVE) of intrinsic clearance of AO and dual AO CYP substrates from a variety of in vitro systems, and the latest research to resolve these. The development of physiologically-based pharmacokinetic (PBPK) models for AO and dual AO-CYP substrates will be presented. In particular, the value and challenges of proteomics abundance data across tissues and population groups, and reverse translation of clinical data will be discussed. Relevance to clinical pharmacology including drug-drug interactions and dose adjustment in specific populations will be discussed.

Speakers:

—Dr Sandhya Subash (Washington State University, WA): "Key Factors Affecting Quality and Translatability of In Vitro AO Mediated Metabolism Data"

—Dr Nihan Izat (University of Manchester, UK): "Current Perspectives on IVIVE Of Aldehyde Oxidase and PBPK Modelling Strategies"

in ISSX for a short period of time. Admittedly, our LMS has not been as popular as anticipated, so we need to do some deliberate thinking to ensure it is a useful tool for our Society. This team will need to be small and focused, and also contain diversity to make sure ideas for improvement come from all viewpoints. If this is something that you are passionate about, please contact the ISSX office at information@issx.org and express your interest.

And as always, if you haven’t done so yet, please remember to renew your membership for 2023. Membership is much more than just discounts on the registration fees to meetings. Unlike other professional scientific organizations that are broad in scope and thus massive, ISSX caters to us in our unique niche of xenobiotic science. We are a special group!

With kinds regards to all,

Scott

Additional webinars will be announced soon! Check the ISSX webinar schedule to stay in the know on upcoming scientific lectures and discussions.

Did you miss a recent webinar? Sign into your ISSX membership account and view all past webinars in the ISSX Learning Center

Do you have an idea for a webinar? Submit a Proposal to Present for the ISSX Webinar Series

We want to hear from you! Complete a brief form online to submit your proposal today . The information presented in the ISSX Webinar must be balanced and provide the attendee with an objective viewpoint. Proposals for the ISSX Webinar will be evaluated for the ability to provide educational content to ISSX members. The scientific content (merit) of the webinar is subject to review and prior approval by the ISSX Continuing Education Committee (CEC) is needed before proceeding.

Save the Date: ISSX/DMDG 2023: The Drug Metabolism Discussion Group and 16th European Meeting of the International Society for the Study for Xenobiotics

June 11–14, 2023

University of Hertfordshire, United Kingdom

Join us in Hatfield, United Kingdom this June!

On behalf of the Meeting Organizing Committee, it is our pleasure to invite you to the DMDG and 16th European Meeting of the International Society for the Study of Xenobiotics (ISSX). This meeting will convene at the University of Hertfordshire, June 11–14, 2023.

This is the first co-organized meeting for DMDG and ISSX, and it provides an extremely valuable and truly unique opportunity for researchers to gather and exchange ideas and expertise. In addition to an outstanding scientific program, the meeting provides you with access to state-of-the-art exhibits and ample opportunities to present your work during our poster presentation sessions.

MEETING ORGANIZING COMMITTEE

Meeting Organizing Committee Chairs: Barry Jones, Pharmaron, Rushden, United Kingdom, Ana Alfirevic, University of Liverpool, Liverpool, United Kingdom, Rachel Rose, Certara, Sheffield, United Kingdom, and Simon Taylor, Pharmaron, Hoddesdon, United Kingdom

MEETING ORGANIZING COMMITTEE MEMBERS: Patrick Dansette, Université de Paris Cité, Paris, France

Christopher Goldring, University of Liverpool, Liverpool, United Kingdom

Scott Obach, Pfizer, Groton, Connecticut, USA

Damjana Rozman, University of Ljubljana, Ljubljana, Slovenia

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REGISTRATION

Your meeting registration grants you access to all keynote, plenary, and concurrent scientific sessions as well as poster sessions, time with exhibitors, and social events. ISSX and DMDG members and ISSX Student/ Postdoc members receive special registration discounts. Join ISSX or renew your membership today to save.

Exhibitor Registration: Interested in exhibiting at the meeting? Exhibitors receive two complimentary registrations with a 10’x10’ booth space. Sponsor with us to receive additional benefits.

Please note: Short courses are offered to fully-registered attendees for an additional fee. Short course session attendees receive access to course materials and a short course attendee lunch. Bundle your short courses and save!

Register today at www.issx2023.org/issx-dmdg/registration

Save the Date: ISSX/DMDG 2023

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Simone Schadt, Roche, Basel, Switzerland

Kunal Taskar, GSK, Stevenage, United Kingdom PRELIMINARY PROGRAM**

Sunday, June 11, 2023

Short Course 1: Physiologically-based Pharmacokinetic (PBPK) Models: Basic Concepts to Advanced Applications

Chairs: Kunal Taskar, GSK and Pradeep Sharma, AstraZeneca

Short Course 2: Pharmacogenomics Basics

Chairs: Ann Daly, University of Newcastle and Ana Alfirevic, University of Liverpool

Short Course 3: The Application of Humanised Models in Drug Discovery and Development and in the Design of Clinical Trials

Chairs: Roland Wolf, University of Dundee and Lorna Ewart, Emulate

Short Course 4: New Modalities, Beyond Rule of Five

Chairs: Simone Schadt, F. Hoffman La Roche, Ltd. and Donglu Zhang, Genentech

Opening Keynote Presentation: Personalized Medicine

Professor Sir Munir Pirmohamed, University of Liverpool

Opening Welcome Reception with Exhibitors and Posters

Monday, June 12, 2023

Plenary Lecture 1: DMDG Fellow Presentation To be announced

Concurrent Symposia 1 & 2

Symposium 1: Harnessing –omics Approaches in Drug Development

Chairs: Jim Monroe, Merck and Co. and Christopher Goldring, University of Liverpool

Symposium 2: Challenges and New Technologies in Delivering Brain Penetrant Therapies

Chairs: Hugh Walton, Astex Theraputics and Scott Summerfield, Pharmaron

Plenary Session 1: Optimisation Challenges of Protein Degraders —Perspectives from DMPK and PK/PD

Modeling

Chairs: Andreas Reichel, Bayer and Dermot McGinnity, AstraZeneca

Plenary Session 2: Use of PK Enhancing Strategies / Co-therapies

Chairs: Nicola Wilsher, Astex Therapeutics and Aram Oganesian Astex Pharmaceuticals

Tuesday, June 13, 2023

Plenary Lecture 2: Use of PBPK in Drug Development

Aleksandra Galetin, University of Manchester

Concurrent Symposia 3 & 4

Symposium 3: Connecting AI/ML and PBPK Modeling for Lead Identification and Optimization in Early Drug Discovery

Chairs: Andres Olivares-Morales, Roche and Yanran Wang, Genentech

Symposium 4: MicroRNAs as Biomarkers of Clinical Drug-induced Organ Injury

Chairs: Chris Goldring, University of Liverpool and Sophia Samodelov, University of Zurich

Plenary Session 3: Free Communications—Breaking Science

Simone Taylor, Pharmaron and Rachel Rose, Certara

Debate

Attendee Networking Dinner

ABSTRACT SUBMISSIONS

Poster presentations are an integral component of ISSX meetings. We encourage all those involved in the fields of metabolism, pharmacology, toxicology, molecular biology and other related disciplines to consider submitting an abstract for a poster presentation at the ISSX/DMDG 2023 Meeting. Please submit your abstract today!

Be sure you’re signed up to get the latest emails from ISSX by visiting issx.org .

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Save the Date: ISSX/DMDG 2023

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Wednesday, June 14, 2023

Plenary Lecture 3: ADME Tactics in the Discovery/ Development of Oral COVID-19 Protease Inhibitors

Amit S. Kalgutkar, Pfizer, Inc

ISSX and DMDG Awards

Plenary Session 4: Microphysiological Systems for ADME Applications Chairs: To be announced

Plenary Session 5: War Stories: Drug Discovery from the Trenches Chairs: Amit Kalgutkar, Pfizer and Simone Schadt, F. Hoffmann La Roche, Ltd.

*Program subject to change.

Welcome New Members

The International Society for the Study of Xenobiotics proudly welcomes the following new members. We greatly appreciate their support and hope that each remains aligned and affiliated with ISSX for many years to come.

2022 NEW MEMBERS

Vikram Krishna Ramanathan , Sun Pharma Advanced Research Company Ltd., Vadodara, Savli, India

Utpal Nandi , CSIR-Indian Institute of Integrative Medicine, Jammu, India

Sai Shyam Kumar N.S. , PSG College of Pharmacy, Coimbatore, Peelamedu, India

Elnaz Gozalpour , Pharmaron UK Ltd, Hoddesdon, Hertfordshire, United Kingdom

Pooja Ponnusamy, Loxo Oncology at Lilly, Longmont, Colorado, United States

Rob Rieger , Cogent Biosciences, Boulder, Colorado, United States

Adam Auclair, Boehringer Ingelheim, Ridgefield, Connecticut, United States

Zhixin Miao , BioCryst, Birmingham, Alabama, United States

Ravikanth Veluri , Lilly, Carmel, Indiana, United States

Shugo Yamashita , Doshisha Women's College of Liberal Arts, Kyotanabe-City, Kyoto-fu, Japan

Joyce Liu , Genentech, South San Francisco, California, United States

Kohei Matsunaga , SUMITOMO CHEMICAL Co.,Ltd., Konohana-ku, Osaka-shi, Osaka, Japan

Maria Chatzopoulou , UCB Biopharma SRL, Slough, United Kingdom

ISSX Focus Groups

ISSX Focus Groups provide ISSX members with a great opportunity to network with your colleagues while discussing topics relevant to the day. Your participation in the ISSX Focus Groups help us to enhance the exchange of the most current scientific research information and open doors to endless opportunities for collaboration and career advancement. View the latest from the ISSX Focus Groups and join today!

BIOANALYSIS IN ADME SCIENCE

The aims of this group include: (a) to promote state-ofthe-art analytical technologies to solve challenging issues faced in ADME studies and bioanalysis, (b) to enable industrial scientists to actively contribute to and participate at ISSX meetings and associated activities, and (d) to enhance synergy between industrial scientists and academic researchers.

BIOTRANSFORMATION, MECHANISMS, AND PATHWAYS

Points for discussion include: (a) metabolism-directed drug design (e.g., incorporation of D to reduce metabolic liability), (b) mechanisms underlying biotransformations that yield “unusual” metabolites and characterization of the metabolizing enzymes responsible for their formation, and (c) idiosyncratic immune-mediated toxicity via metabolism (e.g., reactive metabolites).

MODELING AND SIMULATION

This group focuses on the role of modeling and simulation in drug development in all stages, including topics such as (a) translational extrapolations from preclinical data to clinical expectations, (b) drug-drug interactions, (c) extrapolations of PK/PD data to special populations, (d) early dose optimization, and (e) selection of doses for clinical testing.

TRANSPORTERS

The goals of this focus group are to disseminate and promote state-of-the-art research and foster collaborations among ISSX members on the role of transporters in drug disposition, drug interactions, efficacy, and toxicity, and their impact on drug discovery, development, and regulatory decision making.

UPCOMING EVENTS

The ISSX Biotransformation Mechanisms and Pathways Focus Group has organized a virtual workshop, Small Molecule Metabolites in Drug Discovery and Development from March 1–3. Registration is now open , and you can review the program online , or learn more about this workshop on pa ge 5.

The ISSX Transporters Focus Group is hosting a webinar on March 14 at 10:00 AM ET/15:00 UTC. This webinar will feature talks from Dr. Mengyue (Melody) Yin, University of Washington and Dr. Shawn Pei Feng Tan, University of Manchester. It will also include a robust panel discussion with Dr. Aleksandra Galetin, Dr. Jashvant Unadkat, and Dr. Yuichi Sugiyama.

ISSX Newsletter is published quarterly in the spring, summer, autumn, and winter. For information concerning advertising in this publication, including rates and specifications, please visit issx.org/advertising or contact Scott Narug at snarug@issx.org .

Change of Address

If your mailing address, telephone, fax number, or e-mail has changed or will change, please let us know as soon as possible. You may update your contact information at any time using the online membership directory, which you can access in the Member Only section of the website. If you have forgotten your username and/or password, please contact information@issx.org

Editor

Dr. Allen Cato, III

Vistagen Therapeutics

343 Allerton Avenue South San Francisco, CA 94080

USA

Telephone: +1-650-577-3698

E-mail: jcato@vistagen.com

ADVERTISE WITH ISSX

The quarterly ISSX Newsletter is an online publication featuring Society updates, scientific articles of interest, book reviews, summaries of ISSX meeting proceedings, and more. This publication is designed to update the ISSX membership on the activities and events of the organization and to provide an information forum.

Not only is the ISSX Newsletter promoted directly to all ISSX members, it is also available to anyone who visits the ISSX website.

Visit issx.org/advertising or contact Scott Narug at snarug@issx.org.

ISSX THANKS OUR SPONSORS FOR THEIR GENEROUS SUPPORT: