Screening Drug Transporter Proteins header 

 

About This Conference:

Cambridge Healthtech Institute’s Inaugural conference on Screening Drug Transporter Proteins will cover the latest in the use of 2D and 3D in vitro systems and in vivo models for studying the function, expression and localization of important classes of drug transporters. What transporters to study and when? How physiologically relevant are these systems and how reliable are the predictions made from the data? How can you design assays that are clinically significant and how will the regulatory agencies receive this data? Experts in the field share their experiences leveraging the utility of diverse assays and endpoints, and help address some of the key bottlenecks.



Thursday, October 9

11:30 am Registration


1:00 pm Plenary Keynote Program 
 

Chas BountraChas Bountra, Ph.D., Professor of Translational Medicine & Head, Structural Genomics Consortium, University of Oxford

Martin TolarMartin Tolar, M.D., Ph.D., Founder, President & CEO, Alzheon, Inc.

Andrew L. Hopkins, Andrew L. Hopkins, D.Phil, FRSC, FSB, Chair of Medicinal Informatics and SULSA Research Professor of Translational Biology, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee


2:45 Refreshment Break in the Exhibit Hall with Poster Viewing


UTILIZING RELEVANT IN VITRO ASSAYS AND MODELS

3:45 Chairperson’s Opening Remarks

Yvonne Will, Ph.D., Associate Research Fellow, Compound Safety Prediction, Pfizer Global Research & Development

3:55 Novel Applications of the Sandwich-Cultured Hepatocyte Model for Transporter Investigations

Kim Brouwer, Pharm.D., Ph.D., W.R. Kenan, Jr., Distinguished Professor and Chair, Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill

Sandwich-cultured hepatocytes (SCH) are a versatile in vitro model to assess hepatic drug transport (uptake, basolateral efflux, biliary clearance). Recently, the utility of SCH to quantify intracellular drug/metabolite concentrations, drug interactions in hepatic transport, and the drug metabolism-transport interplay has been demonstrated. Novel applications of SCH as a screening tool to assess phospholipidosis potential and bile-acid mediated drug-induced liver will be discussed.

4:40 Informing the Potential of Drug-induced Liver Injury (DILI): Predictive Models for Bile Acid Synthesis and Disposition

Yurong Lai, Ph.D., Senior Principal Scientist, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company

DILI is a major concern for the pharmaceutical industry. Drug-induced disruption of BSEP function leads to accumulation of bile acids (BAs) in hepatocytes, and subsequently regulates bile acid transport and biosynthesis through feed-forward and feedback regulatory mechanism. Disruption of these complex processes could lead to BA accumulation and liver injury. The presentation will describe the in vitro efforts on bile acid profiling to inform the potential for liver injury.

5:25 Coffee Break in the Foyer

5:40 Developing Cell-Based Assays to Accurately Predict Liver Injury Due to Mitochondrial Toxicity and BSEP Inhibition

Yvonne Will, Ph.D., Associate Research Fellow, Compound Safety Prediction, Pfizer Global Research & Development

For many years we have studied drug induced mitochondrial toxicity in a variety of drug classes. Of those drugs that cause clinical drug-induced liver injury (DILI), we noticed that some of the drugs also inhibited the bile salt efflux pump. We conducted a study and found that indeed dual inhibition correlated with severe human DILI, whereas inhibition of only one or the other had less of a correlate.

6:25 Q&A with Session Speakers

6:40 Close of Day

7:00 Dinner Short Courses*

*Separate registration required


Friday, October 10

7:30 am Registration

8:00 Interactive Breakfast Breakout Discussion Groups 

This interactive session provides conference delegates and speakers an opportunity to choose a specific roundtable discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.

Interpreting Regulatory Guidances

Joseph Polli, Ph. D. Worldwide Director DMPK, GlaxoSmith Kline

Mitchell E. Taub, Ph.D., Senior Research Fellow, Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc.

  • Are regulatory guidances a check box of studies for filing?
  • How does evolving science influence or change existing strategy and guidelines?

Choosing the Right In Vivo Models for Transporter Studies

Maciej Zamek-Gliszczynski, Ph.D., Director, Drug Metabolism and Pharmacokinetics GlaxoSmithKline
Xiaoyan Chu, Ph.D., Senior Principal Scientist, Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism (PPDM), Merck & Co.

  • When are transporter knock-out (KO) animal studies appropriate in drug discovery and development?
  • Proper interpretation and clinical translation of KO and humanized animal model data

Evaluating the Right In Vitro Assays and Models for Transporter Studies

Kim Brouwer, Pharm.D., Ph.D., W. R. Kenan, Jr., Distinguished Professor and Chair
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill

Yvonne Will, Ph.D., Associate Research Fellow, Compound Safety Prediction, Pfizer Global Research & Development

  • Testing new assay reagents and platforms
  • Translating in vitro findings to in vivo predictions
 
TRANSLATING TRANSPORTER DATA INTO IMPROVED UNDERSTANDING

9:00 Chairperson’s Remarks

Toshihisa Ishikawa, Ph.D., President, NGO Personalized Medicine & Healthcare, Yokohama, Japan

9:10 The Use of Genomic and Systems Biology Approaches to Identify Genetic Determinants of Susceptibility to Chemical-Induced Hepatotoxicity

Jose Manautou, Ph.D., Professor of Toxicology, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut

Treatment of rodents with low hepatotoxic doses of acetaminophen (APAP) results in resistance to subsequent, more toxic doses of APAP, termed APAP autoprotection. We are interested in studying the genetic determinants of this heightened tolerance to APAP hepatotoxicity. I will highlight the results of studies analyzing differentially expressed hepatic transporters in the APAP autoprotection model, with emphasis on Mrp4 (ABCC4). The regulatory mechanisms governing such changes and our characterization of the structure and regulation of the Mrp4 gene core promoter will be presented.

9:40 In vitro and in silico Investigations of BCRP Polymorphism on Statin Transport

Mingxiang Liao, Ph.D., Senior Scientist I, DMPK, Takeda Pharmaceutical Intl. Company

The genetic polymorphisms of transporters have been demonstrated to impact the pharmacokinetic and pharmacodynamic properties of drugs. The polarized cell monolayer models that express the wild type or a SNP variant of BCRP, and wild type OATP1B1 were developed and characterized. The in silico simulations were performed to further confirm the hypothesis derived from the cell models. The application of these in vitro and in silico models to assess the effects of BCRP polymorphism on statin transport will be discussed.

10:10 Coffee Break in the Exhibit Hall with Poster Viewing

10:55 Lost in Translation? – A Focus on Renal Transporter Mediated Drug-Drug Interactions

Kari Morrissey, Ph.D., Associate Scientist, Department of Clinical Pharmacology, Genentech, Inc.

Typically, one compares the in vivo Cmax,u of a potential inhibitor to its in vitro IC50 to predict the likelihood for a transporter DDI to occur. However, other factors such as the inhibitor’s half-life and activity against other transporters should also be considered. This presentation will highlight in vitro and clinical studies with promiscuous and selective inhibitors of renal transporters, with a focus on the clinical impact of renal transporter-mediated DDIs.

11:25 Towards an Increased Understanding of the Complex Drug–Drug Interactions Involving OATP Transporters: Recent Experiences and Key Learnings

Xiaoyan Chu, Ph.D., Senior Principal Scientist, Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism (PPDM), Merck & Co.

Inhibition of OATP1B1-mediated hepatic uptake may cause clinically significant drug-drug interactions (DDIs). To assess risk for such DDIs, in vitro approaches, decision trees, and clinical studies have been recommended by the US FDA and EMA (European Medicines Agency). Case studies will be presented which highlight potential complications associated with statin related DDIs. In vitro and in vivo approaches to better understand such DDIs will also be discussed.

11:55 In vivo Models to Bridge the Translational Gaps for Pharmacokinetics Influenced by Hepatic OATPs

Maciej Zamek-Gliszczynski, Ph.D., Director, Drug Metabolism and Pharmacokinetics, GlaxoSmithKline

The fraction of total hepatic uptake mediated by OATP1B1 is key to understanding clinical DDIs and pharmacogenetic variability. Studies with OATP-substrate drugs support the utility of oatp1a/1b-knockout mice in determining whether hepatic OATPs affect drug pharmacokinetics and hepatic distribution. If so, OATP1B1-humanized knockout-mice can be used to accurately predict the fractional contribution of OATP1B1 to hepatic uptake in humans after correcting for protein expression differences be expression differences between humanized mouse and human liver.

12:25 pm Sponsored Presentation (Opportunity Available)

12:55 Session Break

1:05 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:45 Session Break


IN VITRO TO IN VIVO EXTRAPOLATION

1:55 Chairperson’s Remarks

Joseph Polli, Ph.D., Worldwide Director, DMPK, GlaxoSmithKline

2:00 FEATURED PRESENTATION: Drug Transporters, Drug Interactions and Agency Review Experiences

JosephPolliJoseph Polli, Ph.D., Worldwide Director, DMPK, GlaxoSmithKline

With the publication of the International Transporter Consortium Whitepapers and the Drug Interaction Guidances from EMA and FDA in 2013, there has been a surge of research and regulatory activity in the area of drug transporters over the past 12 months. The objective of this presentation is to share a perspective on when transporter related work should be undertaken during drug discovery/development and how this fits with current regulatory guidances.

2:45 Questions from Attendees

3:00 Refreshment Break in the Exhibit Hall with Poster Viewing

3:30 Modulation of OATP1B1/1B3 Uptake Alter Systemic and Hepatic Exposure of Drug Substrates, Right! Think Again

Ayman El-Kattan, Ph.D., Associate Research Fellow, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer, Inc.

Systemic and hepatic exposure of OATP1B1 and 1B3 substrates is governed by different mechanisms. The systemic exposure of these substrates is governed by active uptake as highlighted by the extended clearance concept. However, liver exposure is driven by metabolism/bilairy elimination. This presentation will highlight these principles and substantiate it with in silico/in vitro/clinical drug-drug interactions and pharmacogenomics findings.

4:00 Evaluation of the Interaction of Poorly Permeable Metabolites with Hepatic Uptake and Efflux Transporters

Mitchell E. Taub, Ph.D., Senior Research Fellow, Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc.

To comply with current regulatory guidelines, the potential interaction of major metabolites of investigational drugs with uptake and efflux transporters should be evaluated. However, metabolites are typically more hydrophilic than the parent drug, and due to their lower membrane permeability, may be challenging to study using commonly employed bidirectional transport assays. Two case studies involving late-stage development compounds will be presented.

4:30 Mechanistic Modeling of Drug-Induced Liver Injury that Involves Bile Acid Transport Inhibition: A Case Study with Troglitazone

Kyunghee Yang, Ph.D., Postdoctoral Fellow, The Hamner Institutes for Health Sciences

Drug-mediated functional disturbances in hepatic bile acid transporters leads to intracellular bile acid accumulation and subsequent hepatic injury. DILIsym® is a mechanistic model of DILI that integrates data from different experimental systems and species, and biological knowledge, to predict human DILI. In this presentation, troglitazone will be employed as a model hepatotoxic compound to demonstrate how DILIsym® can be used to predict hepatotoxic potential of compounds that involve bile acid transport inhibition.

5:00 Close of Conference



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2014 Discovery on Target Brochure  

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PREMIER SPONSOR 

Cellecta 

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SPONSORSHIPS & EXHIBITS 

The exhibit hall was sold out in 2013, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2014, contact:

Jon Stroup
Business Development Manager
781-972-5483
jstroup@healthtech.com 

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CONFERENCES


October 8 – 9

Targeting Epigenetic Readers and
Chromatin Remodelers
 

Targeting the Ubiquitin Proteasome System  

Big Data Analytics and Solutions  

GPCR-Based Drug Discovery  

RNAi for Functional Genomics Screening
– Part 1
 

Protein-Protein Interactions as Drug Targets  

Antibodies Against Membrane Protein Targets
– Part 1
 


October 9 – 10

Targeting Histone Methyltransferases and Demethylases  

Screening Drug Transporter Proteins  

Maximizing Efficiency in Discovery  

GPCR-Targeted Therapeutics  

Genome Editing for Functional Genomics
Screens – Part 2
 

Cancer Metabolism  

Antibodies Against Membrane Protein Targets
– Part 2
 


SYMPOSIUM


October 7

Next Generation Histone Deacetylase Inhibitors  


SHORT COURSES


October 7

SC1: Designing Scalable Software Systems for Big Data Analytics  

SC2: Approaches for Biologically-Relevant Chemical Diversity  

SC3: Setting Up Effective RNAi Screens: From Design to Data to Validation  

SC4: Targeting Protein-Protein Interactions  

SC5: GPCR Structure-Based Drug Discovery  

SC6: Advances in Metagenomic Drug Discovery for New Anti-Infective Agents  

SC7: Targeting of GPCRs with Monoclonal Antibodies  

SC8: A Primer to Gene Editing: Tools and Applications  

SC9: Introduction to Targeted Covalent Inhibitors  


October 9

SC10: Setting Up Effective Functional Screens Using 3D Cell Cultures  

SC11: Integration of BDDCS and Extended Clearance Principles  

SC12: Introduction to Allosteric Modulators and Biased Ligands of GPCRs  

SC13: Introduction to Drug Metabolism