- 리드 화합물의 최적화와 약물 독성 예측 -

리드 화합물의 최적화와 약물 독성 예측을 테마로 한 이 컨퍼런스 프로그램에서는 약제 후보의 최적화 작업을 개선하고, 약제 관련 독성을 정확히 예측하기 위한 연구 및 기술개발의 진척 상황이 소개됩니다.

Final Agenda

Recommended All Access Package:

11월 27일: 장기 칩과 미소 생리 시스템

11월 27일 Dinner Course: 쇼트코스 2:약물 대사와 약물 운송의 주요 개념

11월 28-29일: 리드 화합물의 최적화와 약물 독성 예측

11월 29-30일: 3차원 세포 모델

11월 29일 Dinner Course: 쇼트코스 5:인간화 마우스 모델:기술 개요와 암 면역치료의 전임상 평가에 대한 응용

11월 28일(수)

7:00 Registration and Morning Coffee

통합화 리드 화합물의 최적화 전략과 리스크 평가 전략

8:20 Welcome Remarks

Tanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute

8:25 Chairperson’s Remarks

Bernard Faller, PhD, Director, PK Sciences-In vitro ADME, Novartis Institutes for BioMedical Research

8:30 Transport Systems: Victims or Perpetrators in Drug Safety?

Bruno Stieger, PhD, Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland

Adverse drug actions are typically caused after the drugs have entered the cells. This is the standard situation, where drug transporting uptake systems act as perpetrators of adverse drug action. Outside of the cells, drug uptake may be impaired by drug-drug interactions and lead to pharmacokinetic drug-drug interactions with uptake systems being victims. At epithelial barriers like the intestine, drugs may interfere with efflux systems, e.g., which become victims. In hepatocytes, drugs or their metabolites can also interfere with the canalicular efflux of bile salts, making BSEP a victim.

9:00 Screening Strategies for Cellular Uptake

Bernard Faller, PhD, Director, PK Sciences-In vitro ADME, Novartis Institutes for BioMedical Research

Intra-cellular concentration is an important parameter to assess target engagement, especially for teams working outside the traditional LMW property space where permeability might be rate-limiting. What are the assays that can be used to assess intracellular concentration? How long does one need to incubate? How can one most effectively remove non-specific binding? How are efflux and uptake transporters shifting the equilibrium between medium and intra-cellular compartments?

9:30 Sponsored Presentation (Opportunity Available)

10:00 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:45 Reactive Drug Metabolites in Safety Testing of Novel Drug Candidates

Christine K. Maurer, PhD, Head of Laboratory Discovery Biotransformation, Research & Development, Global Early Development, Merck KGaA

Many drugs withdrawn from the market undergo bioactivation to reactive metabolites (RMs). These can form covalent bonds to proteins and/or DNA potentially leading to organ toxicity and/or carcinogenesis. Thus, detection, risk minimization, and integrated risk assessment of RM formation is important in drug discovery and development. In this talk, current methods for RM detection and strategies for risk assessment in oncology projects are discussed in connection with the Merck RM strategy.

11:15 Idiosyncratic Drug Toxicity: Can in silico Tools Predict Bioactivation?

John C. L. Erve, PhD, DABT, Consultant, Jerve Scientific Consulting, Inc.

Idiosyncratic drug toxicity (IDT) remains a concern to pharmaceutical firms and patients. Bioactivation of drugs to reactive metabolites is integral to the Hapten hypothesis. Bioactivation is traditionally investigated experimentally in vitro together with mass spectrometry. Bioactivation has also be investigated computationally. Approaches include quantum chemical calculations, docking with P450 enzymes and more recently, neural networks. In this talk, in silico approaches will be illustrated using drugs that have caused IDT.

11:45 Sponsored Presentation (Opportunity Available)

12:15 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:45 Session Break

생체외 연구에서 생체내 연구로의 중개 개선

13:45 Chairperson’s Remarks

Danilo A. Tagle, PhD, Associate Director for Special Initiatives, National Center for Advancing Translational Sciences, National Institutes of Health

13:50 Use of a Quantitative Systems Pharmacology (QSP) Model to Predict Liver Toxicity in Simulated Populations

Christina Battista, PhD, Postdoctoral Fellow, University of North Carolina Institute for Drug Safety Sciences

DILIsym®, the result of an ongoing public-private partnership, has been developed to investigate drug-induced liver injury (DILI). The model employs mathematical representations of mechanistic interactions following drug administration through the release of serum biomarkers to accurately predict clinical observations in simulated patient populations. This talk will outline DILIsym and discuss applications to date.

14:20 On-/Off-Target and Class Effects of Different Biological Classes and How to Use Them for in silico Modelling of Biologics

Alexander Amberg, PhD, Computational Toxicologist, R&D Preclinical Safety, Sanofi

A wide variety of biotherapeutic modalities are used as drugs, many of them are a relatively new class of therapeutics. There is an uncertainty regarding the adverse effects of the different biological classes, for some people they are just a result of exaggerated pharmacology. This presentation will summarize results of an analysis of on-/off-target and class effects of different biological classes and will try to answer the question if and how they could be used for in silico modelling approaches of biologics.

14:50 Interactive Breakout Discussion Groups

This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Details on the topics and moderators are available on the conference website.

16:00 Refreshment Break in the Exhibit Hall with Poster Viewing

16:45 Microphysiological Systems for Safety and Efficacy Studies

Danilo A. Tagle, PhD, Associate Director for Special Initiatives, National Center for Advancing Translational Sciences, National Institutes of Health

Approximately 30% of drugs have failed in human clinical trials due to adverse reactions despite promising pre-clinical studies, and another 60% fail due to lack of efficacy. The NIH Tissue Chips program is developing alternative approaches for more reliable readouts of toxicity or efficacy during drug development. Tissue chips are bioengineered microphysiological systems utilizing chip technology and microfluidics that mimic tissue cytoarchitecture and functional units of human organs. These microfabricated devices are useful for modeling human diseases, and for studies in precision medicine and environment exposures.

17:15 Development of Quantitative Systems Pharmacology (QSP) for Improved Association of Preclinical and Clinical Treatment Phenotypes

Bérengère Dumotier, PhD, Secondary Pharmacology Expert, Safety Pharmacology, Novartis Pharma AG

Inadequate balance between therapeutic efficacy and adverse events is a major reason for high attrition rates. Majority of adverse events are related to undesirable drug pharmacology (off-target pharmacology, complex pharmacokinetics), and disease-specific pathophysiology of patients. Off-target engagements can be determined at the very early phase of drug discovery processes; however, their translation to AEs is dependent on the two other components mentioned above. The talk will focus on the best way to integrate preclinical and clinical data for small molecules, into a knowledge-based platform for preclinical risk mitigation.

17:45 Immunoallergic Hepatitis

Jürgen Borlak, PhD, Professor, Pharmacology and Toxicology, Institute for Pharmaco- and Toxicogenomics, Hannover Medical School

Hypersensitivity to NSAIDs may result in serious inflammatory reactions of the liver. We investigated the toxicity of diclofenac in mice, dogs and minipigs and compared findings to clinical DILI cases. I present histopathology and serum/urinary biochemistry findings that were corroborated by immunohistochemistry and immunogenomics. The mechanism of diclofenac-induced immunoallergic hepatitis involves activation of the complement system of the classical and alternate pathway. Thus, an erroneous programing of the innate and adaptive immune system results in granulomatous hepatitis and mastocytosis of the liver.

18:15 Welcome Reception in the Exhibit Hall with Poster Viewing

19:15 Close of Day

11월 29일(목)

8:00 Registration and Morning Coffee

의약품 안전성 평가를 위한 줄기세포 이용

8:25 Chairperson’s Remarks

Christopher Goldring, PhD, Senior Lecturer, Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool

8:30 Importance of Phenotyping Your Model to Know What Purpose It Is Fit For

Christopher Goldring, PhD, Senior Lecturer, Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool

It is estimated that 38% and 51% of compounds showing liver injury in man do not show similar effects in animals. The work of the IMI MIP-DILI and TransQST consortia shows how a roadmap is being developed based for the integration of established and emerging test systems and illustrates the increasing complexity of models from 2D to multi-cell 3D systems that are used in a logical fashion to assess DILI liabilities of new drugs before they are given to man.

9:00 Bioengineering Human Pluripotent Stem Cell Derived 3D Models for Drug Toxicity and Disease Modeling

Paula M. Alves, PhD, Unit Director, Cell Bioprocesses Laboratory, Instituto de Biologia Experimental e Tecnologica (iBET)

The development and validation of human in vitro models with physiological relevance, robustness, reproducibility and scalability are still a need in toxicology. Our strategy combines human stem cells, 3D culture strategies and computer-controlled bioreactors in perfusion operation modes. Results concerning the establishment and refinement of culture systems for efficient stem cell differentiation and maturation into cardiac, neural and hepatic cells, as well as their applicability for long-term toxicity testing will be presented and discussed.

9:30 Sponsored Presentation (Opportunity Available)

10:00 Coffee Break in the Exhibit Hall. Last chance for poster viewing.

10:45 Exploring the Relationship Between Myofilament Calcium and Force Production in the Single iPS-Cardiomyocytes

Matthew J Daniels MA PhD, MRCP, Wellcome Trust Intermediate Clinical Fellow, Principal Investigator, Division of Cardiovascular Medicine, and BHF Oxbridge Centre of Regenerative Medicine, Oxford University

The in vitro survival of iPS-CMs should aid cardiotoxicity studies of contractility. As contraction depends on depolarisation, both parameters should be measured in these assays. We find that all classes of chemical dye (voltage, calcium and sodium) impair contractility, and when used in combination with drugs known to act on the myofilament produce confusing composite results making them unreliable for this purpose. We describe how we have overcome this problem.

11:15 Phenotypic Analysis for Cardiotoxicity Evaluation on Human iPSC

Anthony Perrier, PhD, Study Director, In vitro Toxicology, Biologie Servier

To improve the early prediction of cardiac toxicity, we developed in vitro tests using High Content Analysis using human iPSC cardiomyocytes. The readouts were qualified using Receiver Operating Characteristic curves and a ranking algorithm was developed to obtain an overall multiparametric cardiotoxicity evaluation for each compound. This cardiotoxicity phenotypic analysis and ensuing improvements will be used for early safety evaluation in the drug development process at Servier.

11:45 Evaluating Cardiovascular Liability and Genetic Disease with hiPSC-Cardiomyocytes

Chris Denning, PhD, Professor and Head, Department of Stem Cell Biology, University of Nottingham

We will review the results from a public-private partnership (NC3Rs-GSK), termed the “CRACK-IT InPulse Challenge” and the software developed to facilitate analysis of cardiac contractility. This sought to evaluate hiPSC-cardiomyocytes in 2D and 3D formats in the blinded evaluation of 28 drugs that were associated with positive or negative inotropy in heart tissue, or no effect. Finally, we will show data on the coupling of hiPSC-CMs and Cas9/CRISPR-mediated gene editing to model hypertrophic cardiomyopathy.

12:15 Brief Session Break

12:20 Bridging Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:50 Close of Conference

* 주최측 사정에 따라 사전 예고없이 프로그램이 변경될 수 있습니다.

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