Chemical & Pharmaceutical Structure Analysis

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CPSA Shanghai 2012

From Bench to Decision Making - From Basics to Application

April 25 - 27, 2012
Renaissance Shanghai Pudong Hotel
Shanghai, China

Abstract

Wednesday

DMPK Workshop

Workshop Leaders:
Lucy Xu, Novartis
Huan Li, AMMS

Instructors:
Francis Tse
Lawrence Gan, Biogen Idec
Cindy Xia, Millennium
Tonika Bohnert, Biogen Idec
Angela Wong, Merck Serono
Jing Lin, Sunovian
Lucy Xu, Novartis

The Role of DMPK in Exploratory Drug Development

Instructor: Francis Tse
This session of the workshop will focus on the role of drug metabolism and pharmacokinetics in exploratory drug development, the overall goal of which is to increase the probability of ultimate success for a compound entering clinical trials, by demonstrating safety, efficacy, and ability to produce a marketable dosage form. The fundamental concepts of absorption, distribution, metabolism, and excretion will be discussed, with an overview of the typical in vitro and in vivo studies used to evaluate the pharmacokinetic characteristics and underlying mechanisms. Recent advances in related fields such as pharmacogenetics, pharmacogenomics, and drug transport have allowed us to better understand and predict enzyme regulation and its effect on pharmacokinetics, and provide insights into potential drug-drug interactions mediated by enzymes or transporters, as well as inter-individual variability in pharmacokinetics. Novel modeling and simulation tools further facilitate the interpretation of nonclinical data and enable the prediction of pharmacokinetic/pharmacodynamic (PK/PD) outcome in humans.

DDI Overview

Leader: Tonika Bohnert

Screening and Assessing Metabolic Drug Drug Interactions In Vitro

Instructor: Su Zeng
Drug metabolism is one of key factors for determining several pharmacological and toxicological properties of pharmaceuticals and is mediated by drug metabolizing enzymes such as cytochrome P 450, UGT and transporter. Drug interactions represent 3–5% of preventable in-hospital ADRs and nearly always due to interaction at drug metabolizing enzymes and drug transporters. So it is important to screen and asses the potential of adverse drug reactions or toxicity governed by drug metabolism. The metabolic drug-drug interactions can be predicted by in vitro models including hepatic microsomes, recombinant proteins, transgenic cells etc. combined with chemical inhibitors, antibody, RNAi and chemical inducers.

Transporter Mediated Drug Drug Interactions

Instructor: Cindy Xia, Millennium
With a large number of transporters cloned and their functions characterized in in vitro assays and in preclinical animals, the important roles of transporters in drug absorption, distribution, metabolism, elimination, as well as in efficacy and toxicity in humans have been well recognized. Inhibition or induction of transporter can alter the ADME of a co-administered drug, which may lead to drug-induced toxicity or lack of efficacy. Drug-drug interaction (DDI) potential is one of the major factors that cause pharmaceutical failure at either pre-marketing or post-marketing time frames. Prediction of drug-drug interactions from preclinical species and in vitro ADME studies is a critical but challenging task in drug discovery.

This Transporter DDI short course will introduce drug-drug interactions (DDIs) related to drug transporters. Topics covered in this short course include principles for transporters, methods for efflux and uptake transporter substrate evaluations, and assays for transporter inhibitions and inductions in drug discovery and development. The speaker will also share her experience how to interpret the DDI data generated from non-clinical studies, make recommendation to clinical development and help clinical DDI study design.

In Vitro and In Silico Predictions of Drug Drug Interactions

Instructor: Tonika Bohnert
Difficulty in accurately predicting magnitude of drug-drug interaction (DDI) is one of the lead causes of a high incidence of undesirable side-effects of co-administration of drugs in the clinic. Therefore, throughout the course of drug discovery, new chemical entities (NCE) are assessed for their ability to be either a victim of a DDI (mediated by another co-administered drug) or be a perpetrator (or precipitant) of DDI themselves. In most cases, DDIs occur due to inhibition, inactivation or induction of drug metabolizing enzymes and transporters, both of which play a vital role in a drug's disposition. It is a routine procedure to rely on in vitro methodologies and in silico prediction and simulation tools to identify and predict the severity of a DDI and mitigate the risk between co-administered drugs in the clinic. Goal of this presentation is to examine the various in vitro and in silico DDI prediction tools that drug metabolism scientists rely heavily on, and discuss the pros and cons of these methodologies to predict the extent of in vivo DDI.

Roundtable Discussion: Career Development in Pharmacuetical Company

Panelists: Lucy Xu (Facilitator), Francis Tse, Lawrence Gan, Angela Wong, Jing Lin

Biographical Information

Dr. Hua Li (李桦博士) received her bachelor's degree in Pharmaceutical Sciences from Beijing Medical University in 1983, her Master and Ph.D. degrees in Pharmacology from the Academy of Military Medical Sciences (AMMS) in 1986 and 1991. From 1986 to 1997 she worked in the Institute of Pharmacology and Toxicology of AMMS, and became a professor in Dec 1994. She engaged mainly in research and development of new drugs, toxicokinetics studies of toxic chemicals. She was appointed the Head of the Drug Metabolism and Analysis Laboratory of the Institute in 1992. She joined the Organization for Prohibition of Chemical Weapons as an Inspection Team Leader in June 1997 and returned to the AMMS in May 2007. She is currently the professor in the Institute of Pharmacology and Toxicology with the research focus on application of DMPK in new drug discovery and development, drug metabolism mediated drug-drug interaction, and TK of toxicants.

Dr. Lucy Xu (徐晓莹博士) is the Group Head of DMPK at Novartis Institutes for Biomedical Research in Shanghai, China. She is in charge of DMPK-China daily operation, making strategic decision for China project development, providing PKPD support to local clinical trials and multinational clinical trials for China and global registration. Lucy received her B.S. in Pharmacy from Beijing Medical University and Ph.D. in Pharmacognosy from University of Illinois at Chicago. After graduation, Lucy joined Schering-Plough in New Jersey, USA and served as a group leader in DMPK for 8 years. In 2005 and 2007, Lucy received Schering-Plough President Award and Premier Award, respectively. Before joining Novartis, she worked as an associate director of Department of Pharmacokinetics in XOMA (US) LLC in California, USA. Lucy has been very actively participating in DMPK scientific community in China. She is a frequent speaker at various conferences and workshops. She has a tracking record with 30+ manuscripts in peer reviewed journals and authored four book chapters. Lucy is also a certified Project Management Professional.

Dr. Francis L. Tse (谢励诚博士) is Vice President of Drug Metabolism & Bioanalytics at Novartis Institutes for Biomedical Research, overseeing the unit’s strategy and operations in North America and Asia. Dr. Tse received the B.S., M.S., and Ph.D. degrees from the University of Wisconsin-Madison. Following a brief tenure as Assistant Professor of Pharmacy at Rutgers University, Dr. Tse joined the Drug Metabolism Department of Sandoz Pharmaceuticals. He has managed, in positions of increasing responsibility, the preclinical and clinical bioanalytics, pharmacokinetics, and metabolism functions within the department, as well as serving on several disease area decision boards including oncology and infectious diseases. A frequent lecturer on the subject of pharmacokinetics, Dr. Tse has published 130 research articles and is the coauthor or coeditor of five books. He was appointed to the editorial board of Antimicrobial Agents and Chemotherapy, served on two Expert Committees of the United States Pharmacopeia, and is a member of the IQ Consortium Drug Metabolism Leadership Group. In recent years, Dr. Tse has been actively promoting Novartis R&D presence in China. He was an invited lecturer at two GLP Training Workshops organized by the SFDA (Guangzhou 2006 and Hangzhou 2009), the Healthcare Industry Forum (Beijing 2007 and 2010), and a keynote speaker at the 4th China International Life Sciences Summit (Hangzhou 2008). He was appointed Adjunct Professor of Pharmacy at Nankai University, Tianjin, China in 2010. Dr. Tse is a Fellow of American Association of Pharmaceutical Scientists (AAPS), Academy of Pharmaceutical Research and Science (APRS), and American College of Clinical Pharmacology (ACCP). He is a recipient of the prestigious 2006 Outstanding 50 Asian Americans in Business Award.

Dr. Su Zeng (曾苏博士) received his bachelor degree in Pharmacy and Master degree in Pharmaceutical Analysis from Zhejiang Medical University in 1982 and 1986, respectively. He worked on analytical toxicology at Center for Human Toxicology, University of Utah, USA from 1990 to 1992. He then went on to obtain his Ph.D. in Biological Organic Chemistry at Zhejiang University in 1999. Currently he is Professor, College of Pharmaceutical Sciences, Zhejiang University. His research focused on development of analytical method for determining drug and metabolite in biological samples, transgenic CYPs, UGTs, GSTs, Transporters, NRs cells etc for studying the transport，ADME，induction and inhibition, metabolic drug interaction of chemical drug and Traditional Chinese Medicine. (http://mypage.zju.edu.cn/zengsu)

Dr. Cindy Xia is a Sr. Scientist II at Millennium, The Takeda Oncology Company. She received her B.S. (1993) and M.S. (1996) in Medicinal Chemistry from Beijing Medical University (currently Peking University), and her Ph.D. (2000) in Pharmaceutical Sciences from University of Southern California. She joined Millennium in 2001 in Lead Drug Discovery Research and then the Biotransformation group of DMPK. After joined Millennium, Dr. Xia and her team has implemented several transporter related assays in Millennium and played a significant role in providing permeability/transporter support to both discovery and development projects. Since 2008, she has taken the responsibility to support both discovery and development projects with drug-related transporters and metabolism enzyme related studies in Millennium. She continuously builds up and refines many in vitro ADME assays to help projecting human PK and potential drug-drug interactions. She has also been severing as DMPK representatives in different discovery and development projects. Her research interests are focused on understanding the roles of drug related transporters and metabolism enzymes in drug disposition, efficacy, toxicity and drug-drug interactions. Dr. Xia has 26 peer-reviewed publications and many posters and invited presentations. She has been very active in the scientific community of DMPK and has been chairing Biotransformation or ADME sessions at many scientific conferences.

Dr. Tonika Bohnert currently serves as Associate Director of Drug Metabolism and Pharmacokinetics (DMPK) at Biogen Idec, Cambridge, MA. Her group is responsible for in vitro ADME support (metabolic stability, CYP inhibition, plasma/tissue/ microsomal protein binding, CYP mapping, UGT inhibition, UGT mapping) of all small molecule discovery and development projects in Biogen Idec. In addition to her laboratory responsibility she is also responsible for non-clinical DMPK support of multiple projects in early and late discovery stages as well as providing support to investigate ADME, understand DDI issues, and toxicokinetic support of projects in clinical development. Before joining Biogen Idec, she was a post-doctoral associate with Prof. Pete Dedon, in Division of Toxicology at M.I.T., where her research involved detection and quantitation of DNA adducts in-irradiated or enediyne (calicheamycin)-treated DNA via LC/MS/MS and NMR techniques. Before joining M.I.T. she graduated with a Ph.D. in Organic/Bio-organic Chemistry from Department of Chemistry, University of Missouri-Columbia. Her Ph.D. research involved synthesis of cyclic analogs of antitumor antibiotic leinamycin and varacin and study of mechanism of action of DNA damage by these antitumor antibiotics and their analogs. She has co-authored publications and book chapters and is very actively involved in peer-review process of new publications in journals such as Current Drug Metabolism and Drug Metabolism and Disposition. Her major interest involves understanding ADME, mechanistic biotransformation, and drug-drug interactions of small molecules, in discovery and development stages in Biogen Idec.

Dr. Angela Wong is currently the Head of Nonclinical Development, Merck Serono (MS) China. She joined the company in November, 2010 and established the MS R&D Lab in Beijing. The Lab supports the clinical trials conducted in China by analyzing the clinical samples for drug levels and biomarkers, using the most suitable and reliable method. Prior to Merck Serono, Angela spent 5 years as a Vice President at WuXi AppTec and built a world class DMPK team. She grew the department to 200 employees and a strong revenue producer for WuXi AppTec. She also led WuXi team to achieve AAALAC accreditation for the rodent facility in Shanghai and the 320,000 sq ft toxicology facility in Suzhou. Angela is a native of Hong Kong and received both her B. S. and M.S. in Biochemistry from the Chinese University of Hong Kong. She then immigrated to the United States and received her Ph.D. degree in Pharmacology at Baylor College of Medicine. She took a Senior Scientist appointment at Glaxo SmithKline, where she continued her work on prostaglandins, leukotrienes and their roles in inflammation. She participated in several successful programs including GPIIb/IIIa antagonists for anti-thromobosis and v3 antagonists for treatment of osteoporosis and cancer. Both programs resulted in several clinical candidates which showed promising efficacies. She is an inventor on 3 patents and an author on 32 full publications.

Dr. Jing Lin is an associate director in Sunovion Pharmaceuticals Inc. and her responsibilities include leading and influencing projects from discovery to regulatory filing, and from outsourcing strategy to execution for DMPK. Prior to her current position, Dr. Lin was working for Pfizer in DMPK discipline as a senior principal scientist from 2000 to July 2011. Her expertise has been extensively in drug discovery from early exploratory to Phase I clinical trial. She acted as a project leader to make strategic decisions to enhance compounds moving forward using in silico, in vitro and in vivo tools, particular in the therapeutic areas of oncology and infection disease. Prior to Pfizer, Dr. Lin worked at Drug Metabolism Department of Abbott Laboratories, IL from 1997 to 2000. Her scientific expertise includes drug metabolizing enzymes and PBPK modeling (SimCYP and GastroPlus). Dr. Jing Lin obtained a Ph.D. in organic chemistry from Loyola University of Chicago in 1995 and followed by a post-doctoral training in drug metabolism enzymes at University of Washington, Seattle from 1995 to 1997. Dr. Lin has a track record of publication and also has been presenting at many conferences and academic institutions nationally and internationally.

Dr. Wen Chyi Shyu, VP of Drug Metabolism and Pharmacokinetic Department at Millennium: The Takeda Oncology Company, is responsible for developing and executing non-clinical ADME strategy. She is well versed in drug metabolism and pharmacokinetic aspects of drug discovery, development and life cycle management. She is a member of the Leadership Team for Drug Metabolism Leadership Group (DMLG) and a liaison between Drug Metabolism and Clinical Pharmacology Leadership Groups in US PhRMA since 2005.

Dr. Wen Chyi received her Ph.D degree from University of Connecticut in Pharmacokinetics. Prior to joining Millennium, she was in the Metabolism and Pharmacokinetic Department and Discovery Medicine and Clinical Pharmacology department at BMS where she spent 20+ years. She has extensive pharmacokinetic and metabolism experience in pharmaceutical research from drug discovery stage to development stage in both small molecules and biologics compounds. She is involved in various therapeutic areas, i.e. anti-infective, anti-viral, cardiovascular, metabolic diseases, neuroscience, immunology and oncology. She was responsible for DMPK/clinical PK related document in the NDA/MAA/SNDA registration of cefprozil, cefepime, transnasal butorphanol, didanosine, BvaraU, irbesartan, irbesartan/HTCZ, pravastatin, dasatinib, ixabepilone, abatacept, dapagliflozin and brentuximab-vedotin. Her research experience ranges from providing input on an early compound selection to characterization and differentiation of compounds under clinical investigation, and, finally, to the post marketing stage including life cycle management. Over the year, she has more than 80 publications in the peer reviewed journals and book chapters. She has gained a wealth of knowledge not only in the technical aspects but also in global regulatory and marketing issues.

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