Volume 40
Issue 2, 2017
ISSX President’s Message By Geoff Tucker, ISSX President As I write, ISSX is eagerly looking forward to the imminent European Meeting in Cologne and, later in the year, to the North American Meeting in Providence, RI. Uwe Fuhr and his team are to be congratulated on putting together an outstanding program for Cologne; registration is looking healthy and it promises to be an excellent meeting. Similarly, many thanks to Jash Unadkat and Allan Rettie for assembling a stellar line-up of speakers for Providence; register today and keep those abstracts coming in! Looking further ahead to 2018, organization of the 6th Asia Pacific Meeting in Hangzhou, China is well underway and plans are in hand for the 22nd North American Meeting in Montreal, Quebec chaired by Jack Uetrecht.
Establishment of the three Focus Groups has progressed and it has been agreed that the first in-person gatherings of each group will take place at the Montreal Meeting. The webinar program is proving to be highly successful and the next is scheduled for June 6. Entitled “Drug Failures and Lessons for Future Drugs,” this session will be presented by Dennis A. Smith and sponsored by TRL/Lonza. You will have noticed that regular lists of recommended just-published journal articles with links to abstracts are now being disseminated weekly via our Twitter feed and soon they may be viewed on the homepage of the ISSX website. This is based on monthly input from Mike Zientek, Jas Sahi, Cyrus Khojasteh, Scott Obach
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and myself. We will be monitoring this initiative, which we hope is proving useful to members. There was some discussion at Geoff Tucker, Ph.D. the last Council ISSX President. telecon as to a vision for social functions at ISSX Meetings. Do we need to have more informal options? Clearly, it would be difficult to emulate baseball at Gordon Conferences and, for those of you who are old enough to remember, soccer followed by sponsored whisky tasting at the Continued on next page
The ability to present my research and get feedback from leaders in the field as well as meet others who were working on similar projects was invaluable. —Past ISSX Meeting Abstract Presenter
Poster presentations are an integral component of ISSX meetings. We encourage researchers 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 21st North American ISSX Meeting to be held in Providence, Rhode Island from September 24–28, 2017.
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Elevate your profile by having your research abstract published in a peer reviewed journal and contribute to the learning of others by presenting at the meeting. Don’t delay. Submit your abstract by June 18, 2018 to issxna2017.org.
President’s Message Continued from previous page Stowe School Meetings in the UK—but ISSX would like to hear your (constructive) opinions. Finally, a few ‘presidential ruminations and inspirational thoughts.’ While research on the fate of xenobiotics continues to progress, unfortunately these days it is difficult to ignore the increasing impact of politics on the conduct of our science. Internationally, those with an anti-science agenda are becoming increasingly vocal and nationally there are specific issues of current concern. For example, in the US, significantly decreased government funding of research is on the table and in the UK the impact of Brexit and restrictions on the use of expensive new drugs by the National Health Service looms over the future of research and the
location of Pharma companies and European and UK medicines regulation. All the more reason for supporting independent, international scientific organizations like ISSX. We must stick together with a communal voice, developing our membership by embracing a greater spectrum of expertise as drug discovery and development becomes increasingly complex and by expanding our attention to the risks imposed by chemicals in a changing natural environment. As ever, ISSX encourages comments from its members as to how it may serve them better. I hope to see you in Cologne and Providence as well as at our other future ISSX meetings.
Sr. Principal Scientist, Analytical & Viral Assay Development
Inhalation Toxicologist–In Vitro Model
Sr. Principal Scientist, Analytical & Viral Assay Development Senior Scientist–DMPK Representative, Immuno-Oncology PKPD Modeling
Inhalation Toxicologist–In Vitro Model
These are just a few of the titles of open positions you will find on the ISSX Career Center. Job seekers can view and apply for positions and upload their CV to have recruiters reach out to make that perfect match. Employers are strongly encouraged to place job announcements on the ISSX Career Center to broaden
Scientist I/II, Cellular Pharmacology
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Senior Scientist–DMPKRepresentative, Immuno-Oncology PKPD Modeling Scientist I/II, Cellular Pharmacology
Scientist I/II, Cellular Pharmacology
Scientist I, DMPK
/ISSX Newsletter / Issue 2, 2017
Sr. Principal Scientist, Analytical & Viral Assay Development
Scientist I, DMPK
ISSX Helps Employers and Job Seekers to Connect
Scientist I, DMPK
Senior Scientist–DMPK Representative, Immuno-Oncology PKPD Modeling
their search and to support ISSX and our community. Our Career Center products include basic postings as well as connections to leading science job boards worldwide. View the options available today and post with ISSX to reduce the duration of your open positions.
Get started today at issx-jobs.careerwebsite.com.
Book Review DRUG METABOLISM IN DISEASES Editor; Wen Xie Elsevier–Academic Press 294 pp, ISBN-13: 978-0-12-802949-7. 2017 The effect of disease or ongoing general ill health, a raised temperature or inflammatory response and frailty in the elderly, are often overlooked in their potential influence on the metabolism of drugs that may be administered to such individuals. This book highlights these problems and imparts experience and information as to how to predict effects on drug metabolism during these differing pathophysiological states. The volume is divided into eleven segments with each addressing a theme within this important issue. The first chapter entitled, ‘Introduction of Drug Metabolism and Overview of Disease Effects on Drug Metabolism,’ concerns itself with enzymemediated bio-transformations, protein binding, blood flow to organs, absorption processes, and transporter expression. The next two chapters specifically discuss the inflammatory response and its untoward effects. The following sections are concerned with the specific problems associated with kidney disease, liver disease and cardiovascular disease and examine the efficacy of drugs (sulfonylureas, meglitinides, metformin, thiazolidinediones, a-glucosidase inhibitors, DPP-4 inhibitors) in patients with type 2 diabetes mellitus. The critical care scenario is tackled as well as the potential effects of pregnancy and hepatic drug metabolism in pediatric patients. The final chapter is entitled, ‘Xenobiotic Receptors in the Crosstalk between Drug Metabolism and Energy Metabolism’ and outlines the
concept of xenobiotic receptors as ‘master regulators’ of drug metabolism and the interplay between drug metabolism and energy metabolism within the organism. Specifically, this latter missive is concerned with the constitutive androstane receptor (CAR), the pregnane X receptor (PXR) and the aryl hydrocarbon receptor (ACH) and their role in transcriptionally regulating the expression of drug metabolising enzymes and transporters. Each chapter is around 24 pages in length, the shortest (14 pages) being that focussing on estrogen-metabolising enzymes in systemic and local liver injuries and incorporating case studies. Overall, the 23 contributors (USA 15, China 4, Canada 2, the Netherlands 2) from industry and academia have constructed an interesting and useful tome covering an important but underplayed aspect of drug metabolism. The book is recommended for all those interested in drug and xenobiotic metabolism and situations that may arise and alter the status quo.
Reviewed by
Steve Mitchell Faculty of Medicine Imperial College London London SW7 2AZ, UK
Book Ordering Information Academic Press Elsevier 525 B Street, Suite 1800 San Diego, CA 92101-4459 USA 125 London Wall London EC2Y 5AS UK
Issue 2, 2017
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ISSX Welcomes New Members The International Society for the Study of Xenobiotics is proud to welcome the following new members. We greatly appreciate their support and hope that each remains aligned and affiliated with ISSX for many years to come. Ghadah Alghaith, University of Rhode Island, United States
Erkka Järvinen, University of Helsinki, Finland
Miina Ruokolainen, University of Helsinki, Finland
Jane Angeles, Dart Neuroscience Inc., United States
Hayley Jones, Cyprotex, United Kingdom
Anitha Saravanakumar, Univeristy of Rhode Island, United States
Usman Arshad, University Hospital Cologne, Germany
Katsuhiro Kanda, Hitachi HighTechnologies Corporation, Japan
Matthew Sherman, Lonza, United States
Mohammed Atari, Cyprotex Discovery Ltd., United Kingdom
Thomas Kirmeier, HMNC Brain Health, Germany
Pu Shi, Takeda, United States
Sarah Billington, University of Washington, United States
Annett Kühne, PortaCellTec Biosciences GmbH, Germany
Manushi Siddarth, University College of Medical Sciences & GTB Hospital, India
Christopher Bradfield, University of Wisconsin, United States
Takuya Kuno, Otsuka Pharmaceutical Co., Ltd., Japan
Chantale Simard, Université Laval, Canada
Yu-Luan Chen, Sunovion Pharmaceuticals, Inc, United States
Mayur Ladumor, National Institute of Pharmaceutical Education and Research, India
Neeru Singh, University College of Medical Sciences, India
Harvey Chin, Novartis Pharmaceuticals, United States
Volker Lauschke, Karolinska Institutet, Sweden
Estela Skende, Sunovion Pharmaceuticals, Inc., United States
Younghee Choi, Dongguk University, Korea
Mi-Young Lee, Unilever R&D, United Kingdom
Joseph Tillotson, Johns Hopkins School of Medicine, United States
Katherine Cisneros, University of Florida, United States
Ji Young Lee, Yecuris, United States
Julia Tschirka, Germany
Catarina Coelho, UCIBIO, Portugal
Fengping Li, Pfizer, United States Marleen Meyer, Germany
Elaine Tseng, Pfizer Inc, United States
Franck Da-silva, Sanofi/ INSERM, France Victorien Delannée, IRISA, France Paul Donabella, Albany Molecular Research, Inc., United States Yilin Dong, Alkermes, United States
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Andrew Felts, Vanderbilt University, United States
Mario Mezler, AbbVie Deutschland GmbH & Co KG, Germany Astrid Milic, Fidelta, Croatia Kathy Mosure, Bristol-Myers Squibb, United States Dung Nguyen, GlaxoSmithKline, United States
Laura Francis, CAPKR, United Kingdom
Kotaro Nishiyama, Nippon Boehringer Ingelheim Co., Ltd, Japan
Lyrialle Han, University of Washington, United States
Eric Novik, Hurel Corporation, United States
James Harrison, United Kingdom
Magnus Ölander, Uppsala University, Sweden
Sinem Helvacıo˘ g lu, Yeditepe University, Turkey
David Pearson, Novartis, Switzerland
Eef Hoeben, BioNotus, Belgium
Oliver Poetz, NMI, Germany
Yongqing Huang, Achillion Pharmaceuticals, United States
David Ponting, Lhasa Limited, United Kingdom
Sami Ullah, University of Cologne Germany, Germany Matthew Walsh, Albany Molecular Research, Inc., United States Guy Webber, Envigo CRS Limited, United Kingdom Christine Wegler, Uppsala University, Sweden Yuan Wei, Jiangsu University, China Monika Wientzek, Wientzek Associates, United States Sibylle Wilbert, Gilead Scineces, Inc., United States Lili Yao, Forma Therapeutics, United States Julianne Zaremba, Albany Molecular Research, Inc. (AMRI), United States Yongjie Zhang, VU University Amsterdam, Netherlands
GÜRZENICH | COLOGNE, GERMANY | 26—29 JUNE 2017
Register before 24 June 2017 and save!
issxeuro2017.org MEETING ORGANIZING COMMITTEE Uwe Fuhr, Meeting Organizing Committee Chair, Department of Pharmacology, Center for Pharmacology, University Hospital Cologne, Germany Thomas Baillie, ISSX President-Elect/Secretary, University of Washington School of Pharmacy, USA Dirk Gründemann, Department of Pharmacology, Center for Pharmacology, University Hospital Cologne, Cologne, Germany Dieter Lang, Bayer AG, Drug Discovery, DMPK-Drug Metabolism, Wuppertal, Germany
Scott Obach, Pfizer, Inc., USA Stefan Oswald, Department of Clinical Pharmacology, Center of Drug Absorption and Transport, Universitätsmedizin Greifswald, Greifswald, Germany Jens Riedel, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany Gerhard Schänzle, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
Mario Monshouwer, Janssen Research & Development, Belgium
Matthias Schwab, Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany
Edmund Maser, Institute for Toxicology and Pharmacology for Biologists, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
Fritz Sörgel, Institute for Biomedical and Pharmaceutical Research, Nuremberg-Heroldsberg, Germany Geoff Tucker, ISSX President, University of Sheffield, United Kingdom
SHORT COURSES This meeting will offer attendees an opportunity to register separately for up to two short courses. One short course will be held in the morning, followed by a complimentary lunch for all course attendees and the two concurrent afternoon short courses. Short Course 1: Primary Human Hepatocytes: Basic Aspects Primary human hepatocytes (PHH) exhibit unique complexity and diverse functions: they contain a broad complement of metabolizing enzymes and transport proteins organized in a physiologically relevant context. The function of PHH strongly affects pharmacokinetics, side effects and toxicity of drugs. In this course the basic aspects of PHH use and function, and what they can offer in R&D is explained. The course will thus cover topics such as handling of hepatocyte cultures and their use for prediction of drug metabolism, transport and toxicity, different systems for long term cultivation with regard to predicting clearance and metabolite formation as well as an introduction to quantitative in vitro-in vivo modeling. Short Course 2: Advanced Culturing of Human Hepatocytes Cultures of primary human hepatocytes (PHH) are routinely used in drug development to evaluate metabolic fate, drug-drug interactions and drug toxicity. The supply of PHH is however limited and the longevity of PHH cultures is short due to the rapid de-differentiation of hepatocytes in 2D cultures causing a change
of cell function including low expression of ADME genes. In this session, new approaches are presented that elongate the lifespan of PHH and mimic in vivo like functions and possibilities for studying liver diseases, chronic drug toxicity, time dependent enzyme inhibition and long term drug metabolism in vitro. The systems include organs on a chip models, microengineered liver perfused platforms, bioprinted 3D liver tissues and 3D liver spheroids. Short Course 3: Quantifying the in vivo Activity of Human Drug Metabolizing Enzymes and Transporters The activities of individual human drug metabolizing enzymes and transmembrane transporter proteins often represent the ‘bottlenecks’ determining key pharmacokinetic properties of small molecule drugs and other xenobiotics. While these activities can be quantified in vitro, the complexity of the human body as well as various sources of variability prevent direct transfer to the complete organism. Accurate quantification of enzymes and transporters activities in vivo (phenotyping) is therefore essential to predict the pharmacokinetics of respective substrates as well as the effect of an intervention (e.g., drug therapy, diet) or a condition (e.g., genetic polymorphism, disease) thereon. Phenotyping is typically done by administration of a selective substrate of the respective enzyme/transporter and subsequent assessment of suitable pharmacokinetic parameters (‘metrics’, e.g., hepatic clearance or renal secretion) reflecting their (local) activity. continued on next page
14th European ISSX Meeting | Cologne, Germany | 26–29 June 2017 SCIENTIFIC PROGRAM The scientific program is subject to change. View the current program online at issxeuro2017.org/program.
Monday, 26 June 2017 Short Course 1: Primary Human Hepatocytes: Basic Aspects Chairs: Magnus Ingelman-Sundberg and Astrid Nörenberg Hepatocytes—What They Can Do in ADME Research
In vitro Drug Metabolism in Different Hepatocyte Systems—a Comparison Hepatocytes – Use in Clearance and Transporter Studies Cytotoxicity Evaluation Using Primary Human Hepatocytes and Beyond Long Term Hepatocyte Incubations for the Assessment of the Clearance of Metabolically Stable Compounds Toxicokinetics in Quantitative in vitro-in vivo Extrapolation Short Course 2: Advanced Culturing of Human Hepatocytes Chairs: Magnus Ingelman-Sundberg and Astrid Nörenberg
Tuesday, 27 June 2017 Symposium 1: Indication-Specific Challenges for Drug Discovery and Development Chairs: Mario Monshouwer and Olaf van Tellingen Challenges in Antibiotic Drug Development The Importance of Mechanism-Based Drug Disposition in the Discovery and Development of Hepatitis B/C Drug Delivery to Glioblastoma Challenges in the Development of Safe and Effective Immunomodulators Symposium 2: Integrated Pharmacogenomics Chairs: Matthias Schwab and Henk-Jan Guchelaar U-PGx—Ubiquitous Pharmacogenomics: A European Initiative to Implement PGx into Clinics Pharmacoepigenomics and its Impact for Renal Cancer Pharmacogenomics and Brain Metabolism
Introduction to Different Hepatic Models
Symposium 3: Risk Assessment and Regulatory Expectations of Nucleotides in Drug Development Chairs: Tommy B. Andersson and Jesper Christensen
Microengineered Liver Platforms for Multiple Applications in the Drug Development Pipeline
Biodistribution and Metabolism Studies of Lipid NanoparticleFormulated Internally [3H]-Labeled siRNA in Mice
Bioprinted 3D Primary Liver Tissues
VEGF-A Modified mRNA – Risk Assessment and Expectations of a Novel Therapy for Patients with Ischemic Vascular Disease
Novel Physiological 3D Systems for Studies of Human Hepatic Metabolism under Normal and Diseased Conditions
Regulatory Aspects of Oligonucleotide-Based Therapeutics
Human Liver-on-chip Model for the Development of New Therapeutic Options in Treatment of Inflammation-related Liver Failure
Symposium 4: Approaches to Quantify the in vitro Function of ABC Efflux Transporters Chairs: Dirk Gründemann and Yohannes Hagos
Short Course 3: Quantifying the in vivo Activity of Human Drug Metabolizing Enzymes and Transporters Chairs: Uwe Fuhr and Thomas Ebner
Validation of FDA and EMA Recommended ABC-Transporter Assays
Current Approaches and Applications of Phenotyping Methods for Drug Metabolizing Enzymes and Transporters Endogenous Bile Acid Metabolites as Biomarkers for CYP3A Detection of Novel Biomarkers for Drug Metabolizing Enzymes and Transporters Using Global Metabolomics
Assessment of ABC Transporter Function and Expression in the Blood Brain Barrier Innovations in Functional Assessments of Renal ABC Efflux Transporters in vitro
Endogenous Biomarkers for Drug Transporters
Symposium 5: Strategies to Improve Drug Safety in Clinical Development Chairs: Adam F. Cohen and Oliver Cornely
Probe Drug Cocktails to Assess Transporter Activity in Humans: Concept, Probe Selection and in vitro Evaluation
Lessons to be Learned from the BIA-102474-101 Clinical Trial Disaster
Pharmacokinetic Evaluation of Transporter Probe
Adverse Outcome Pathways as Tools to Assess Drug-Induced Toxicity
Drugs in vivo and their Combination in a Cocktail Microdosing, Limited Sampling Strategies, and Continuous Infusion of Substrates: Suitable Techniques to Improve Enzyme / Transporter Activity Assessment
Clinical Development Strategies in First-in-Human Trials of Antineoplastic Agents Improving Drug Safety with a Systems Pharmacology Approach
Caveat: Validation and Limitations of Phenotyping Methods for Drug Metabolizing Enzymes and Transporters
Symposium 6: Recent Technology Advancements Relevant for Drug Discovery and Development Chairs: Ron Heeren and Matthew Blatnik
Keynote Lecture: Ribosomes as Targets for New Antibacterials Daniel N. Wilson, Biochemistry and Molecular Biology, University of Hamburg
The Application of State-of-the Art Mass Spectrometry-Based Molecular Imaging Approaches
Opening Welcome Reception
Probing Cellular Metabolism with Stable Label Isotope Tracing Mass Spectrometry in the Presence of Xenobiotics Pharmacometabolomics: Integrating Clinical Metabolomics and Clinical Pharmacology to Enable Precision Medicine Application of Exome Sequencing and iPSCs to Uncover Mechanisms of Drug Toxicity continued on next page
14th European ISSX Meeting | Cologne, Germany | 26–29 June 2017
State-Of-The Art Lecture 1: Drugging Undruggable Targets Peter Wipf, University of Pittsburgh
Wednesday, 28 June 2017 State-Of-The Art Lecture 2: CYP2D6: A Paradigm for Understanding Genetic Variability in DMPK Andrea Gaedigk, Children’s Mercy Hospital
Thursday, 29 June 2017 Symposium 11: Acquisition and Implementation of DDI Information Applicable for Individual Treatment Chairs: Janne Backman and Uwe Fuhr Clinical Trial Designs to Study Complex Drug-Drug Interactions Assessing DDI Relevance Using Large Databases: From Social Media to Published Literature
Symposium 7: New Investigators’ Forum: Skills Needed for DMPK Scientists Chairs: Stefan Oswald and Bhagwat Prasad Introduction
Algorithms Used by the SFINX (Swedish, Finnish, INteraction X-referencing) DDI Database to Assess Clinical Relevance and Level of Evidence
Project Management: Experiences from a Young Scientist
Doing the Right Things and Doing Things Right: Tips and Tricks for Relevant and Efficient Inpatient DDI monitoring
Scientific Writing / Editorial Processing How to Get Your Research Funded?—Funding Options in the EU Biostatistics and Bioinformatics DMPK Skills Required in the Pharmaceutical Industry Symposium 8: PBPK Beyond PK of Small Molecule Drugs Chairs: Geoff Tucker and Thomas Eißing PBPK of Antibodies A PBPK/PD Model of Glucose Homeostasis A PBPK Model Describing the in vivo Distribution of Administered Mesenchymal Stem Cells A PBPK Model to Describe Dioxin Exposure Across Gestation and Lactation Symposium 9: The Impact of Disease States on Drug Metabolising Enzymes and Transporters Chairs: John Miners and Tommy B. Andersson Drug Renal Metabolism and the Effects of Renal Dysfunction on Metabolic Clearance Human in vitro 3-Dimensional Proximal Tubule Tissues to Study Drug Transporter Pharmacology in Renal Dysfunction Effect of Obesity on Drug Disposition Symposium 10: P(esticide)MPK and Human Health Risk Assessment Chairs: Alan Boobis and Jan Hengstler Assessing Pesticide Metabolites of Concern
Symposium 12: Non-Standard Enzymes in Drug Metabolism Chairs: Edmund Maser and Dieter Lang Carbonyl Reductases / Steroid Dehydrogenases: Biology, Classification, and Implication in Drug Metabolism and Detoxification Human Aldo-keto Reductases: Steroid Hormone Action and Polycyclic Aromatic Hydrocarbon Activation Highly Variable Expression of CYP1A1 in Human Liver and Impact on Pharmacokinetics of Drugs in Humans Significance of Arylacetamide Deacetylase on Drug Metabolism and Toxicity The Mitochondrial Amidoxime Reducing Component (mARC) Involved in Detoxification of N-hydroxylated Structures ISSX Awards Session Plenary Symposium 13: Understanding and Targeting the Human Microbiome Chair: Jonathan Swann Regulation of Host Gastrointestinal Physiology with a Focus on the Interactions Between the Microbiome, Gut, and the Brain Drug-Antibiotic Interactions in the Gut Using Live, Genetically Modified Microbiota as Therapeutics Relationship Between Gut Microbiome and Dynamic Patient Metabolomic Phenotypes State-Of-The Art Lecture 3: The Promises and Challenges of Cancer Epigenetics Daniel Neureiter, Paracelsus University
Incorporation of Knowledge of Integrating Toxicokinetics into Human Health Risk Assessment for Agrochemicals: A Proposed Framework and Case Studies Reassessment of Inter-species and Interindividual Differences in PK/TK for Pesticides The Future of P(esticide)MPK Meeting Banquet at The Gir Keller (Separate ticket fee applies)
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14th European ISSX Meeting | Cologne, Germany | 26–29 June 2017
Join Us at the Gir Keller
Register now: issxeuro2017.org/register
Located just 300 meters from the meeting venue, the historic Gir Keller is one of the oldest vaulted beer and wine cellars in Germany. Our meeting banquet will transport you back in time to a setting with rustic basalt pillars, brick ceilings, and rough stone walls evoking the history of this unique setting. Constructed between 1195 and 1280, monks originally used this impressive vault as a wine cellar. Join us for a buffet dinner with unlimited wine and beer, entertainment, and the company of your fellow meeting attendees.
Registration Fees (includes German VAT)
This is a ticketed event. The registration fee for this event is $89 for students and $137 for non-student attendees. The fee includes 19% German VAT tax (value added tax). To attend, please add the event ticket to your registration.
Registration Information The meeting registration fee includes admittance to: • Scientific Sessions • Awards Presentation Sessions • Keynote Lecture and Plenary Sessions • Poster Presentations • Printed Abstract Book • Exhibition Hall • Welcome Reception • Daily Lunches Tuesday - Thursday • Refreshment Breaks • Attendee List The short courses and meeting banquet at the Gir Keller are separately ticketed offerings and may be added to a registration for an additional fee.
Short Courses Regular On-Site through 23 June 24 June—29 June All Prices in US Dollars ISSX Member $280 $310 Nonmember $334 $375 Student Member $149 $179 Student Non-Member $179 $209
Meeting Registration Regular On-Site through 23 June 24 June—29 June All Prices in US Dollars ISSX Member $887 $952 Nonmember $1,083 $1,137 Student Member $357 $387 Student Non-Member $387 $417 Guest $50 $50
Please note: The meeting registration fee does not include access to the short courses or the meeting banquet at the Gir Keller. Guest registration includes admission to the opening welcome reception and all refreshment breaks. Guest registration does not include admittance to the scientific sessions or the banquet at the Gir Keller. Tickets to the banquet may be purchased for guests in advance.
General Information Cologne Cologne provides the perfect backdrop to the 14th European ISSX Meeting. Founded by the Romans in 50 AD, Cologne has been and continues to be a center of art, culture, history, sports, and academia in Northern Europe. Supplement your time at the 14th European ISSX Meeting by exploring the city and its surroundings, discovering the soul of this jewel on the river Rhine. Review ISSX’s Top Five must-dos in Cologne to make your plans for visiting Cologne: issxeuro2017.org/cologne.
For complete details about this meeting go to www.issxeuro2017.org.
The 2017 ISSX European Scientific Achievement Award The 2017 European Distinguished Scientific Achievement Award is presented to an ISSX member who has made major scientific contributions to the field. The purpose of this award is to recognize meritorious contributions by senior or mid-career scientists who have had a major impact on research in the area of drug metabolism and pharmacokinetics. It signifies achievement and delineates the best of the best within the region. ISSX is extremely proud to bestow this year’s award upon Ann K. Daly, Professor of Pharmacogenetics at the Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. Professor Daly received her PhD from the University of Dublin (Trinity College), performing biochemical studies on aldo-keto reductases and glutathione S-transferases under the direction of Dr. Tim Mantle. She subsequently worked on nuclear structure at the University of Geneva with Professor Ulrich Laemmli and then moved to Newcastle University, working initially on the molecular biology of retinoic acid action. In 1989, she joined the newly formed Pharmacogenetics group at Newcastle. Her current research is focused on the pharmacogenetics of the human cytochrome P450, genetic susceptibility to adverse drug reactions and the genetics of complex diseases, particularly liver disease. Dr. Daly has had a major impact in the direction of the research in the area encompassing the interests of ISSX including:
enomics of Liver Disease: Professor Daly has shown •G that genotype for a common variant in PNPLA3 is an important risk factor for progression of both alcoholic liver disease and non-alcoholic liver disease to fibrosis and hepatocellular carcinoma. A variant in TM6SF2, another gene coding for a protein relevant to lipid processing, was also demonstrated to be a risk factor for progression to fibrosis. •S tudies on Retinoid Biology: She demonstrated the existence of the nuclear receptor RARalpha which binds alltrans retinoic acid (prior to its subsequent cloning by others). Later, she performed studies on the role of cytochrome P450 isoforms in all-trans retinoic acid metabolism showing a key role for CYP2C8. Following detection and characterisation of novel CYP2C8 alleles, she demonstrated that CYP2C8 variant alleles do not account for interindividual variation in 13-cis retinoic acid pharmacokinetics. Ann Daly is Chair of IUPHAR (The International Union of Basic and Clinical Pharmacology) Drug Metabolism and Transporter Section Executive Board; a member of the IUPHAR Pharmacogenetics Subcommittee; Continued on next page
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•P harmacogenetics of Warfarin: Professor Daly showed that those with CYP2C9 alleles associated with decreased activity had a lower warfarin dose requirement and an increased risk of bleeding
rug-induced Liver Injury - Pharmacogenomic •D Studies: She has identified a number of novel genetic predictors of drug-induced liver injury, a rare but serious complication of treatment with a range of widely prescribed drugs. In particular, she has demonstrated the importance of certain HLA alleles, especially HLA-B*57:01, in predicting susceptibility but also demonstrated a drug-specific role for genes relevant to drug disposition (e.g. UGT and ABCC2). She leads the iDILIC consortium which aims to identify novel genetic factors contributing to druginduced liver injury and involves European and other international investigators.
Issue 2, 2017
• I dentification of novel alleles and characterization of genotype-phenotype relationships for CYP2D6. She contributed to the discovery of the main CYP2D6 variant alleles associated with the poor metabolizer phenotype and performed detailed studies on phenotype-genotype relationships. She also led the development of a nomenclature scheme for CYP2D6 alleles which continues to serve as a basis for this P450 gene and genes encoding other P450 isoforms.
when treated with this drug. She subsequently demonstrated that the VKORC1 gene also affected dose requirements and devised dosing algorithms incorporating both genotypes. More recently, she was a member of a consortium that tested a genotypebased dosing algorithm in a clinical trial and found that incorporating genotype in dosing was associated with a significantly improved clinical response.
Scientific Achievement Award Continued from previous page
Committee Member of the UK Pharmacogenetics and Stratified Medicine Network; Editor of The Human Cytochrome P450 (CYP) Allele Nomenclature Database; Executive Editor of the British Journal of Clinical Pharmacology; and an Editorial Board Member of Clinical Pharmacology & Therapeutics, Pharmacogenetics & Genomics, Journal of Pharmacology & Experimental Therapeutics, Pharmacogenomics, Pharmacogenomics Journal. She also has given much of her past time in service to ISSX as a member of Council.
To recognize and celebrate Dr. Daly’s substantial and sustained scientific contributions to the field of xenobiotic disposition spanning more than four decades, she is awarded the 2017 ISSX European Scientific Achievement Award. Dr. Daly will receive the award and deliver the award lecture at the 14th European Meeting of ISSX on June 29, 2017.
CALL FOR NOMINATIONS
Awards We ask members of ISSX to consider nominating deserving candidates for the highest awards ISSX bestows at its North American Meetings. The North American Scientific Achievement Award is named in Honor of Ronald W. Estabrook and was made possible by a donation from XenoTech. This award is presented to an ISSX member who has made major scientific contributions to the field within the North American Region.
The 2017 North American New Investigator Award is named in honor of James R. Gillette. It is presented to an ISSX member who has made significant contributions to the field within the North American Region. These awards include an honorarium, travel support to attend the meeting, a marble plaque, and a place among other leaders who have previously been awarded these honors:
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North American Scientific Achievement Award, in Honor of Ronald W. Estabrook: 2015 2014 2012 2011
Leslie Z. Benet Thomas Baillie R. Scott Obach Paul Hollenberg
2009 Daniel Liebler 2008 Eric Johnson 2006 Frank Gonzalez
2005 Allan Rettie 2003 F. Peter Guengerich 2002 Masa Negishi
North American New Investigator Award, in Honor of James R. Gillette: 2014 Nina Isoherranen 2012 Emily Scott 2009 Chantal Guillemette
2008 Wen Xie 2005 Rachel Tyndale
2003 Steven Kliewer 2002 Richard Kim
Nominate a deserving member today! The submission deadline is July 14, 2017. www.issx.org/awards/nominations
ISSX Webinars Keep Members Informed
An exclusive benefit of membership in ISSX is complimentary access to our live and recorded “on-demand” virtual learning forums. The ISSX Webinar Series brings members the most current information across a variety of topics delivered by the world’s leading experts.
• T he Use of “Extended Clearance Concept” and PBPK Modeling to Interpret Clinical Outcomes from In Vitro Metabolism and Transport Data; Focusing on the Transporters in the Liver Yuichi Sugiyama, Ph.D., Sugiyama Laboratory, RIKEN Innovation Center
Connect to our previous webinars: •D rug Failures and Lessons for Future Drugs Dennis Smith, Ph.D.
• T he Use of BDDCS to Predict Drug Disposition in Drug Development of NMEs Leslie Z. Benet, Ph.D., University of California San Francisco
We are always seeking ideas for topics, speakers who would like to deliver an ISSX webinar, and from industry partners who would like to sponsor a future session. Contact us at information@issx.org for more information.
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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.
Issue 2, 2017
• Physiochemistry and ADMET Dennis Smith, Ph.D.
•B iosynthesis of Drug Metabolites for Use in DMPK Experiments and Late-Stage Lead Diversification R. Scott Obach, Ph.D. and Greg S. Walker, Ph.D., Pfizer, Inc.
Which Meetings do YOU Plan to Attend? The scientific meetings organized by ISSX provide exceptional opportunities for members of the scientific community to exchange ideas and expertise, to develop a common vision, and to create and nurture collaborations in fields related to the study of chemicals that are foreign to the human body. We offer the chance to present your research via multiple formats at our meetings that we hold in North America, Asia, and in Europe.
Short courses at our meetings, presented on a variety of important topics, are a popular way to gain invaluable training. Scientific symposia tracks offer a multitude of options and forums for attendees to learn the most recent developments incorporating the newest ideas and the most current evidence. The chance to view the latest product lines and learn about the services of the companies participating in the trade exhibitions drive even more value to your investment. Moreover, the people that you will meet at our
21st North American ISSX Meeting Rhode Island Convention Center Providence, Rhode Island, USA September 24–28, 2017 Meeting Chairs: Jashvant Unadkat, Ph.D. and Allan Rettie, Ph.D.
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22nd North American ISSX Meeting Palais des congrès de Montréal Montreal, QC Canada July 15–19, 2018 Meeting Chair: Jack Uetrecht, M.D., Ph.D.
meetings are extraordinary. They are contributing to the expanding base of knowledge crucial to broadening the understanding of the effects of drugs, the mechanism of their actions, and the movement of drugs throughout organisms. Please be sure to include funds in your training budget for you as well as your scientific team and participate in our very high quality meetings that are organized by teams of leading educators and investigators worldwide:
6th Asia Pacific ISSX Meeting Zhejiang University Hangzhou, China May 11–15, 2018 Meeting Chairs: Su Zeng, Ph.D., and Jasminder Sahi, Ph.D.
12th International ISSX Meeting Portland Convention Center Portland, Oregon, USA July 29–August 1, 2019 Meeting Chairs: Aleksandra Galetin, Ph.D., Hiroyuki Kusuhara, Ph.D., and Deepak Dalvi, Ph.D.
23rd ISSX North American and 35th JSSX Meeting Hilton Waikoloa Village Waikoloa, Hawaii, USA October 4–8, 2020 Meeting Chairs: Allen Rettie, Ph.D. and Hiroshi Yamazaki, Ph.D.
ISSX seeks proposals from members who may wish to organize scientific meetings. Individuals who wish to organize an ISSX meeting are welcome to submit a proposal and contact the Scientific Affairs Committee via ISSX Headquarters at least 4-5 years in advance of the contemplated date of the meeting. For more information, go to www.issx.org/submit.
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Present your work at the meeting. Submit an abstract by June 18, 2017! www.issx2017na.com Make plans to join us at the 21st North American Meeting of the International Society for the Study of Xenobiotics in Providence, Rhode Island, USA, September 24–28, 2017. Chaired by Jashvant Unadkat and Allan Rettie of the University of Washington, this meeting provides attendees access to short courses, symposia, keynote and plenary sessions, state-of-the-art exhibits, industry-organized sessions, an opening reception, a session designed by and for new investigators, and an optional evening event at a unique roof-top site near our meeting venue—the Rhode Island Convention Center. Our headquarters hotel, the newly renovated landmark Omni Providence Hotel, connects to the convention center and offers our meeting attendees style and comfort at a special reduced rate. We invite you to enhance this meeting by contributing to the scientific component as a participant in the poster program—including the opportunity to present a short podium presentation. Moreover, you have the opportunity
to present a digital version of your poster in our new E-Poster Theater. To participate in the scientific program, please review the information and instructions on the meeting website carefully and submit your abstract by June 18, 2017. Participation in this meeting is a wise use of your training funds. You and your colleagues will gain new insight from important scientific and educational sessions on drug metabolism, drug transport, small and large molecules, toxicology, pharmacology, molecular biology, and related topics while engaging with others working on drug/ xenobiotic research in diverse areas including basic and clinical pharmacology and therapeutics, toxicology, oncology, endocrinology, physiology, biochemistry, molecular and structural biology, and more. We look forward to enjoying this charming part of New England to learn, renew past Acquaintances, and meet new colleagues at the 21st North American ISSX Meeting.
MEETING ORGANIZING COMMITTEE Jashvant Unadkat, Chair University of Washington
Anshul Gupta Alnylam Pharmaceuticals
Yurong Lai Bristol-Myers Squibb
Allan Rettie, Co-Chair University of Washington
Marcel Hop Genentech, San Francisco
Andrew Parkinson XPD Consulting
Aleksandra Galetin University of Manchester
Nina Isoherranen University of Washington
Be Part of the Meeting—Submit an Abstract and Present Your Research ISSX meetings showcase the work of investigators presenting cutting-edge research on the latest advances in topics related to metabolism, pharmacology, toxicology, molecular biology, and other related disciplines during abstract poster sessions. Presenting a poster allows investigators to share their findings and receive feedback from colleagues. Benefits of presenting a poster at the 21st North American ISSX Meeting include: •A ccepted abstracts of original work will be published in a top ranked peer reviewed journal.
Geoff Tucker, ISSX President University of Sheffield Ping Zhao Bethesda, Maryland
•M eet international experts in the field of xenobiotic research and discuss your work during dedicated viewing and presentation times while receiving feedback from colleagues, faculty, and peers. • I nvestigators meeting certain criteria are eligible to participate in the Poster Awards Competition and win prizes and recognition. We have categories for both graduate students and postdoctoral researchers. Be a part of the 21st North American ISSX Meeting program and submit an abstract by Sunday, June 18, 2017. View more information about the poster awards and general poster presentations at issx2017na.com/abstracts.
•S ubmitting an abstract affords opportunities to put your research on the world stage.
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MEETING PROGRAM Program is tentative and subject to change
SUNDAY, SEPTEMBER 24 Short Course 1: Reaction Phenotyping—Methods and Regulatory Requirements for Identifying the Role of Phase 1 and Phase 2 Enzymes in Drug Disposition Short Course 2: Metabolism-Mediated Toxicity: Importance, Prediction, and Evaluation Short Course 3: The Basics of Predicting Clearance Mechanisms for Human PK in Drug Discovery and Development and the Application of Extended Clearance Classification Systems
Symposium 6: Transporters and Enzymes: Novel Insights into the Regulation of Drug Disposition and Response Symposium 7: Molybdenum Coenzymes (e.g. AO and XO) – Basics and Application Symposium 8: Interplay of Transporters and Mitochondrial/ Lysosomal Drug Sequestration–Implications in Toxicity, Efficacy and Drug-Drug Interactions
WEDNESDAY, SEPTEMBER 27 Plenary Lecture 3: Making Drugs Great Again: Eliminating Idiosyncratic Drug Reactions Symposium 9: Mitochondrial Metabolism, Transport, and Toxicity
Short Course 4: Predicting Human Transporter-related Clearance and Drug-Drug Interactions (DDIs) as Currently Practiced in Regulatory Agencies and Industry
Symposium 10: Hydrolases: Enzymology and Role in Drug Development
Opening Keynote Lecture: Regulatory Science: Evolution of a Discipline
THURSDAY, SEPTEMBER 28
MONDAY, SEPTEMBER 25 Plenary Lecture 1: Targeting the Achilles Heel of Cancer: Nutrient Transporters Symposium 1: Towards Understanding of Tissue Transporter Interactions: Impact on Drug Efficacy/Safety and Tissue Targeting Symposium 2: Drug Discovery and Development in the Trenches Symposium 3: Biomarkers of Safety and DDI (Transport and Metabolism) Symposium 4: When is a PBPK Model Fit for Purpose? Insights to Model Acceptance Criteria, Extrapolation to Different Populations, and Modeling Population Variability
TUESDAY, SEPTEMBER 26 Plenary Lecture 2: Cancer Immunotherapy: Checkpoint Inhibitors, Adoptive Cell Therapy, and Beyond Symposium 5: ADME/PK Considerations for Next Generation Therapeutics: ADCs, Antibodies, Oligonucleotides, and Liposomes
Plenary Lecture 4: Pharmacogenomics to Pharmaco-omics: Precision Medicine and Drug Response Symposium 11: New Insights into P450 Structure, Emerging Transporters, and Application to Drug Development Symposium 12: Emergent Technologies for Evaluating Drug and Xenobiotic Disposition Providence, Rhode Island's capital city, was founded in 1636 and is one of the oldest cities in the United States. Although one of the first cities to industrialize, Providence is known today as a center for education, the arts, and culture. Supplement your time at the 21st North American ISSX Meeting by exploring the city or schedule a tour of the mansions of the gilded age in nearby Newport. The Rhode Island School of Design Museum features rotating displays of original art by RISD students as well as classics from the masters. Great dining abounds in part due to the famed Johnson and Wales culinary school located in the city. We’re sure you’ll find Providence an enjoyable city to visit. Be sure to go to www.issx2017na.com for details on lodging, registration, and more!
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Deadline for the submission of material to the ISSX Office: ISSUE
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Issue 3, 2017
July 7, 2017
August 2017
Issue 4, 2017
November 3, 2017
December 2017
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Editor Dr. Allen Cato, III Cato Research, LTD 6480 Weathers Place, Suite 104 San Diego, California 92121 USA Telephone: +1-858-452-7271 Fax: +1-858-452-7784 E-mail: jcato@cato.com
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