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Volume 38

Issue 3, 2016

ISSX President’s Message By Geoff Tucker, ISSX President A lot has been happening in the Asia-Pacific Region in the last few months. The 11th International ISSX Meeting—held in Busan, Korea this past June—was attended by nearly 900 registrants who enjoyed a strong scientific program and social networking events. Congratulations to Professor Jae-Gook Shin and the Meeting Organizing Committee for a job well done. It is also a pleasure to report that the Indian Society for the Study of Xenobiotics (SSX India) has now been established thanks to the sterling efforts of Murali Subramanian, Jasminder Sahi, and their colleagues. The Society’s inauguration was celebrated at a highly-successful initial conference in Bangalore, India in September with more than 200 attendees, representation from the ISSX Council as program speakers, and robust and enthusiastic discussions after every session. We are delighted that the Chinese Society for the Study of Xenobiotics

(CSSX) is leading efforts to organize the 7th Asia-Pacific ISSX Meeting in 2018. Watch for more information soon! I am proud to represent ISSX at the upcoming meeting of the Japanese Society for the Study of Xenobiotics (JSSX) in Matsumoto, Japan, October 13–15 with a presentation on the historical involvement of Japanese colleagues in ISSX, and I look forward to sharing elements of the current ISSX strategic plan. Of note is the recent decision by Council to publish future ISSX meeting abstracts in Drug Metabolism and Pharmacokinetics, the official journal of JSSX. With regard to other upcoming ISSX conferences, the preparations for the 2017 meetings in Cologne, Germany in June and Providence, Rhode Island in September are well in hand, and the respective chairs, Uwe Fuhr and Jashvant Unadkat, have been working diligently on the final programs and speaker invitations. The upcoming ISSX Workshop: Translating Preclinical

Data to Human Clearance and Pharmacokinetics will convene October 27–28, 2016 in Boston, Massachusetts, and we look forward to a great turnout.

Geoff Tucker, Ph.D. ISSX President.

The recently-introduced ISSX webinar program has kicked off with seminal presentations from Leslie Benet on the Use of BDDCS to Predict Drug Disposition in Drug Development of NMEs and Scott Obach on Biosynethsis of Drug Metabolites for Use in DMPK Experiments and Late-Stage Lead Diversification. Yuichi Sugiyama most recently presented on the 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 on September 27. Discussions Continued on next page


Book Review Upcoming Meetings

5 6

ISSX Welcomes New Members Join ISSX in Boston this Fall

President’s Message Continued from page 1 are also underway to host a webinar on the topic of endogenous markers of drug metabolizing enzymes and transporters. Plans to establish member Focus Groups within ISSX are progressing. Council has recently approved the establishment of groups under the headings of Biotransformation Mechanisms and Pathways, and Modelling and Simulation. A third group clustered around aspects of Bioanalytical Sciences is also proposed, but its title is still under discussion in order to reflect major contemporary elements around hyphenated methodologies and imaging. These Focus Groups have several purposes, namely to foster the involvement of and communication between ISSX members, to encourage new membership in the Society, to provide specific input into conference program planning and on-line education initiatives, to develop position papers on emerging issues relevant

to the fate of xenobiotics, and to enhance interaction and collaboration with other societies interested in xenobiotics. The last point is especially important given the fact that several other organizations (AAPS, IQ, and FIP, to name a few) already have similar focus groups. Participation in the ISSX Focus Groups will be free to members, who may choose to join one or more groups. The job descriptions of the chairs and co-chairs of each group have been agreed upon, and ISSX President-Elect Tom Baillie and I will announce the initial appointments shortly. Subsequently, future chairs and co-chairs will be appointed by the members of each group. Last, but not least, please join me in congratulating the newly elected members of the ISSX Council on their recent appointments—Aleksandra Galetin from the United Kingdom, Natalie Hosea from the United States, and Jasminder Sahi from China.

RENEW YOUR ISSX MEMBERSHIP FOR 2017 ISSX’s membership term runs on an annual basis beginning January 1 and ending December 31. Membership dues for the 2017 membership year must be remitted on or before December 31, 2016. To ensure uninterrupted membership benefits, please renew your ISSX membership today! You may renew online by visiting


/ISSX Newsletter / Issue 3, 2016

Your membership indicates your support of our mission to advance research and education on the interplay of living systems with medicines and chemicals for the benefit of society worldwide and helps sustain our program of operations. Thank you in advance for your continued support of the Society!

JOIN THE ISSX NEW INVESTIGATOR FORUM Have you joined ISSX’s New Investigator Forum? The forum was established to encourage new investigators to network and share ideas, research, photos, and more! Please visit and sign in with your ISSX username and password to join the forum and to learn more. We encourage you to leave feedback on what features you would like to see and how ISSX can better serve our community of graduate students and recent postdocs.

Book Review COMPREHENSIVE ANALYSIS OF PARASITE BIOLOGY: FROM METABOLISM TO DRUG DISCOVERY Editors: S. Müller, R. Cerdan, O. Radulescu, P. M. Selzer John Wiley and Sons Inc. 592 pp., ISBN: 978-3-527-33904-4, 2016 Unlike the tomes of years gone by which stood as classical and authoritative works in their own right for many years, several publishers nowadays have initiated a series of volumes to cover particular aspects or facades of specialised areas of science and additions are published at frequent intervals, some tackling further issues and others serving to update the previous missives. A series entitled, ‘Drug Discovery in Infectious Diseases’ has an upcoming volume addressing the underlying physiology and biochemistry of protozoic parasites and their potential exploitation for the design and production of antiparasitic drugs. This intriguing volume, which is number seven in the series, contains twenty-two chapters that cover a vast area of relevant research.

There is some extremely interesting information in this volume. One intriguing nugget is the mechanism of protozoan movement—the glideosome, “a macromolecular complex consisting of adhesive proteins that are released apically and translocated to the posterior pole of the parasite by the action of an actomyosin system anchored in the inner membrane complex of the parasite” (Keeley and Soldati 2004, Trends Cell Biol 14, 528-532). Fascinating, and what a target this presents. As the promotion literature asserts, “this is a must-have for all professionals dealing with drug discovery in parasitology.” A well-constructed book, reasonable font size, easy to (physically) read. A good quality production, as has come to be expected from John Wiley and Sons.

Reviewed by

Steve Mitchell Faculty of Medicine Imperial College London London SW7 2AZ, UK

Book Ordering Information: John Wiley and Sons Corporate Headquarters 111 River Street Hoboken, NJ 07030-5774 United States of America Telephone: 201-748-6000 Fax: 201-748-6088 Email:

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The Atrium Southern Gate, Chichester West Sussex PO19 8SQ England Telephone: +44 1243 779777 Fax: +44 1243 775878 Email:

Issue 3, 2016

The chapter headings are as follows: “Discovering the mechanism of action of novel compounds that target unicellular eukaryotic parasites,” “Contribution of natural products to drug discovery in tropical diseases,” “Isoxazolines as effective ectoparasiticides,” “Trypanosomal cysteine proteases: Target validation and drug design strategies,” “Potential of pyrimidine metabolism for antitrypanosomal drug discovery,” “The Kennedy pathways for phospholipid biosynthesis in Plasmodium,” “Immunophilins as possible drug targets,” “Autophagy in Plasmodium/invasion of Plasmodium,” “The glideosome: The locomotive complex behind gliding motility and invasion,” “Turnover of glycosomes in trypanosomes: Perspectives for drug discovery,” “N-Myristoyltransferase as a target for drug discovery in malaria,” “Intermediary carbon metabolism of Plasmodium revisited,” “The role of metabolomics in antiparasitic drug discovery,” “Methods to investigate system biology in Trypanosoma,” “The importance of targeting lipid metabolism in parasites for drug discovery,” “Epigenetic gene regulation: a key to development and survival of malaria parasites,” “Emerging importance of t-RNA synthetases as anti-malarial drug targets,” “Understanding protozoan parasite metabolism and identifying drug targets through flux balance analysis,” “Attacking blood-borne parasites with mathematics,” “Kinetic modeling of metabolism and drug target

identification in Apicomplexa,” “Antiparasitics from algae,” and “Mechanisms regulating transcription in Plasmodium falciparum as targets for novel antimalarial drugs.”

Save the Dates and Make Plans to Join ISSX at our Upcoming Meetings

2016 ISSX Workshop Sheraton Boston Hotel

14th European ISSX Meeting

21st North American ISSX Meeting

Boston, Massachusetts, USA October 27–28, 2016 Workshop Co-Chairs: Yingying Guo, Ph.D. and Jin Zhou, Ph.D.

Gürzenich Köln

Rhode Island Convention Center

Cologne, Germany June 26–29, 2017 Meeting Chair: Uwe Fuhr, Ph.D.

Providence, Rhode Island, USA September 24–28, 2017 Meeting Chair: Jashvant Unadkat, Ph.D.

22nd North American ISSX Meeting

12th International ISSX Meeting

23rd North American ISSX and 35th JSSX Meeting

Palais des Congrès de Montréal

Portland Convention Center

Hilton Waikaloa Village

Montreal, QC, Canada July 15–19, 2018 Meeting Chair: Jack Uetrecht, M.D., Ph.D.

Portland, Oregon, USA July 29–August 1, 2019

Waikaloa, Hawaii, USA October 4–8, 2020 Meeting Co-Chairs: Allan Rettie, Ph.D. and Hiroshi Yamazaki, Ph.D.



/ISSX Newsletter / Issue 3, 2016

Supplement your learning by attending ISSX's online educational webinars, featuring world-renowned speakers and cutting-edge science. This benefit is offered exclusively to ISSX members. Past webinars and speakers include: • The Use of BDDCS to Predict Drug Disposition in Drug Development of NMEs by Leslie Z. Benet, Ph.D. • Biosynthesis of Drug Metabolites for Use in DMPK Experiments and Late-Stage Lead Diversification by R. Scott Obach, Ph.D. • 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 by Yuichi Sugiyama, Ph.D. Additional information on upcoming webinars will be available soon. Please visit to learn more.

ISSX Welcomes New Members Christian Atsriku, Celgene Corp., United States Sachin Bansal, ASB Life Sciences, Pvt. Ltd., India Priscilla Brun, Sanofi, France

Veera Raghava Choudary Palacharla, Suven Life Sciences, Ltd., India Dae-Hun Park, Dongshin University, South Korea

Christina Chan, University of Liverpool, United Kingdom

Yuna Park

Anna Cieslak, Laval University CHUQ Research Center, Canada

Carl Petersson, EMD Serono, Germany Martin Phillips, ScitoVation, LLC, United States

Rebecca Dargue, Imperial College London, United Kingdom

Katy Saide

Biplab Das, Ariad Pharmaceuticals, United States

Frank Scheffler, Hypha Discovery, Ltd., United Kingdom

Jin Dong, United States

Jayant Sancheti, Tata Consultancy Services, India

Zhongqi Dong, FDA, United States

Chandra Shekhar Sharma, Bhupal Noble's College of Pharmacy, India

Michael Elliot, Achillion Pharmaceuticals, United States

Donggwan Shin, South Korea

Douglas Ferguson, AstraZeneca, United States

Prasad Skr, Dr. Reddy's Laboratories, Ltd., India

Sanjeev Forsyth, Ironwood Pharmaceuticals, United States

Katherine Witt, Triangle Research Labs, United States

Suma Gopinathan, Lexicon Pharmaceuticals, United States

Zhengyin Yan, Genentech, United States

Latoya Griffin, East Carolina University, United States Chandrashekhar Honrao, Northeastern University, United States Chiahsiang Hsueh, United States Huh, Kyobo Life, South Korea Jong-Woo Jeong, Chungnam National University, South Korea Lee Jisoo Donghyeok Kang, South Korea Taeheon Kim, Daewoong Pharm, South Korea Maja Lambert, LEO Pharma, Denmark Richard Lee, Advanced Chemistry Development, Canada Chao Li, Takeda, United States Venkateswari Muthukrishnan, Certara Software India, Pvt. Ltd., India Anantha Naik Nagappa Nagappa, SCS College of Pharmacy, India Onyi Ofoma, Ascendance Biotechnology, United States Yuya Ono, Sekisui XenoTech, LLC, United States Karin Otte, Merck, United States Karen Owens, Merck, United States Noemi Paguigan, University of North Carolina at Greensboro, United States

Joseph Zolnerciks, SOLVO Biotechnology, United States

CALLING ALL NEW INVESTIGATORS! Are you an ISSX Student Member or Regular Member within the first ten years of receiving your highest earned degree? Would you like to be featured in ISSX Newsletter’s New Investigator Spotlight? We’d love to hear from you! Please contact ISSX at to indicate your interest in participating in this new opportunity.

CHECK OUT THE ISSX CAREER CENTER With the ISSX Career Center, over 1,000 jobs in industry and academia are at your fingertips! Visit to learn more about recently-posted jobs applicable to your expertise and set up personalized job alerts to help you manage your career!

/ISSX Newsletter / 5

Satheeshkumar Nanjappan, NIPER Hyderabad, India

Miyoung Yoon, ScitoVation, LLC, United States

Issue 3, 2016

Yuexia Liang, Merck, United States

Jaydeep Yadav, Temple University, United States

Join ISSX in Boston this Fall Attend the ISSX Workshop: Translating Preclinical Data to Human Clearance and Pharmacokinetics, October 27–28, 2016 in Boston, Massachusetts, USA! Pharmaceutical scientists, academicians, and regulatory professionals interested in learning about prediction approaches, developing their expertise, and gaining a more complete appreciation of using a model-based approach to better understand predicting PK/clearance are encouraged to attend this workshop. A poster session will highlight cutting-edge methodologies in human PK/ clearance prediction.


/ISSX Newsletter / Issue 3, 2016


Our ability to accurately predict human clearance and pharmacokinetics (PK) is a critical component of drug discovery and development. These predictions impact projection of first human dose and potential for drug-drug interactions, which are important attributes of the riskbenefit assessment framework for candidate selection and the planning of early clinical studies. Furthermore, consideration can be given to the need for dose adjustment in patients vs. healthy volunteers and for special populations such as pediatric, hepatic or renallyimpaired, and genetic subpopulations. Predictions can be challenging as a result of potential in vitro-in vivo discrepancies and inter-species differences in the specificities and abundance of enzymes and transporters. Moreover, new challenges for human PK/clearance prediction continue to arise. For example, CYP-mediated clearance is being reduced by chemical manipulation in drug discovery only to be replaced by clearance by drug metabolizing enzymes with which we have less scaling experience. This workshop aims to provide fundamental knowledge on current approaches, examine the utility of in vitro and in vivo experimental systems, discuss modeling approaches in human PK/clearance prediction, focus on the current challenges, and offer next steps. The ultimate goal is to facilitate formulation of practical strategies utilized in the pharmaceutical industry for human PK/ clearance prediction based on in vitro and animal data, in combination with modeling methods.

•E  xamine state-of-the-art in vitro technologies, combined with physiologically-based models, to address clearance prediction for low clearance and highly bound compounds • Address challenging issues and next steps in PK/ clearance prediction for non-CYP enzymes, including UGTs, aldehyde oxidase, and carboxylesterases • Discuss approaches to predict human hepatobiliary transporter-mediated clearance • Examine experimental and modeling/simulation approaches in predicting PK/clearance in special populations for compounds of different BDDCS categories

WORKSHOP ORGANIZING COMMITTEE Yingying Guo, Co-Chair, Eli Lilly and Company Jin Zhou, Co-Chair, Boehringer Ingelheim Aleksandra Galetin, University of Manchester Stephen D. Hall, Eli Lilly and Company Donald Tweedie, Merck


*Program is subject to change. View the full program and session timing outline at

Thursday, October 27

Session 1: Short Course: Introduction to Fundamentals and Challenges in Human PK/Clearance Prediction Chair: Yingying Guo, Eli Lilly and Company Predicting in vivo Clearance of Drugs from in vitro Data: Where Are We and Where Are We Going? Jashvant Unadkat, University of Washington

Key objectives include:

Pathways toward Human Clearance Prediction: Better Tools, Fewer Rules Daniel Mudra, Eli Lilly and Company

• Update  the current status and challenges in prediction of human PK • Assess the application and regulatory perspectives of PBPK modeling

Continued on next page

Physiologically-based Pharmacokinetic (PBPK) Modeling to Support Decisions in Drug Development Ping Zhao

Session 5: Human PK/Clearance Prediction in Special Populations Chair: Jack Cook, Pfizer, Inc.

Session 2: Methodological Aspects of Clearance Prediction for Low Clearance and Highly Bound Compounds Chair: Jin Zhou, Boehringer Ingelheim

Case Studies Showing Application of PBPK Modeling for Prediction of PK in Patients with Hepatic and Renal Impairment Karen Rowland Yeo, Certara

Prediction for Low Clearance Compounds: Challenges and State-of-the-Art Tools Scott Obach, Pfizer, Inc.

PBPK Model Extrapolation to Pediatric Population: Querying Uncertainty, Defining a Role for Experimentation, and Current Practices Andrea Edginton, University of Waterloo

Prediction of Volume and Intracellular Concentrations for Highly Protein Bound Compounds Using Traditional and Novel PBPK Framework Swati Nagar, Temple University Session 3: Predicting Non-CYP Metabolizing Enzymes Mediated Clearance Chair: Scott Obach, Pfizer, Inc. Prediction of Hepatic and Extrahepatic UGT-mediated Clearance and Corresponding Drug-drug Interaction Risk within PBPK Paradigm Aleksandra Galetin, University of Manchester How to Use in vitro and Computational Data to Estimate Clinical Outcomes for Aldehyde Oxidase Jeff Jones, Washington State University Application of in vitro and Animal Approaches to Predict Clearance Mediated via Carboxylesterases Li Di, Pfizer, Inc. Welcome Reception with Exhibitors

Friday, October 28

Session 4: Quantitative Assessment of Hepatobiliary Transporter-mediated Clearance Chair: Aleksandra Galetin, University of Manchester Utility and Challenges of in vitro Systems and Modeling Approaches in Prediction of Biliary Clearance Kim Brouwer, University of North Carolina

Visit to reserve your seat at this exciting workshop. Registrant Type

Price (USD)

ISSX Member


Student/Predoctoral ISSX Member




Student/Predoctoral Non-Member



The Sheraton Boston Hotel is a contiguous part of the landmark Prudential Center/Copley Place Complex. The hotel is located just four miles from Boston Logan International Airport and under one mile from the Boston Back Bay (BBY) Amtrak Station. ISSX Workshop attendees are eligible to receive the exclusive rate of $265 USD/night, exclusive of taxes. To reserve a room, please visit Book/ISSX16 online or contact the Sheraton Hotel by telephone at +1-866-716-8134. The attendee rate is subject to availability and may not be available after Wednesday, October 5, 2016.


You’re invited to advance your brand and raise your company’s profile by supporting this important and timely scientific workshop. Both exhibit and sponsorship opportunities are available. Visit exhibit to learn more.

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Predicting and Verifying Transporter-based Systemic and Tissue PK of Drugs Using Proteomics and PET Imaging Jashvant Unadkat, University of Washington


Issue 3, 2016

Evaluation of Preclinical Animal Models to Bridge the Translational Gap for Predicting Hepatic Transporter-mediated PK and DDIs Xiaoyan Chu, Merck

Role of Pharmacogenetics-based Mechanistic Modeling in Early and Late Phase Clinical Studies Manuela Grimstein

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 or contact Steve Rabeor at

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

Deadline for the submission of material to the ISSX Office: ISSUE



Issue 4, 2016

November 1, 2016

December 2016


Subject to change

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:

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 or contact Steve Rabeor at

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