Translation of in vitro ADMET Science to in vivo: Current Perspectives and Challenges | An ISSX and IQ Consortium 2021 Virtual Workshop Event

Translation of in vitro ADMET Science to in vivo: Current Perspectives and Challenges | An ISSX and IQ Consortium 2021 Virtual Workshop Event

This workshop has been organized through the efforts of the  Workshop Organizing Committee  under the leadership of the Workshop Chairs, Christopher Gibson and Lei Zhang, and was jointly sponsored by ISSX and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). 

This workshop brings together scientists from academia, industry, and regulatory agencies in an interactive format to discuss contemporary topics in applied small molecule enzyme and transporter research. We are planning sessions covering not only laboratory and analytical challenges associated with studying enzymes and transporters in vitro, but also challenges and potential solutions/best practices in translation of in vitro ADMET data to in vivo drug disposition and clinical drug-drug interactions (DDIs). There are a mixture of presentations, including overview of the challenges in each research area, rapid-fire talks, followed by roundtable discussion sessions.

The workshop includes access to all presentation slides and recordings.

  • Session 1: Biological, Experimental and Methodological Challenges Associated with the Study of Drug Metabolizing Enzymes
    Contains 6 Component(s)

    The sessions will cover laboratory and analytical challenges associated with studying enzymes and transporters in vitro, as well as challenges and potential solutions/best practices in translation of in vitro ADMET data to in vivo drug disposition and clinical drug-drug interactions (DDIs).

    Chairs: Christopher Gibson, Merck & Co., Inc., West Point, Pennsylvania, USA and Adrian Fretland, Repare Therapeutics, Cambridge, Massachusetts, USA

    Methods to Understand the Role of Gut and Liver CYP and UGT in Human PK Variability and DDI 
    image Yingying Guo, Eli Lilly and Company, Indianapolis, Indiana, USA 

    Can we accurately measure free fraction of highly bound compounds for use in DDI risk assessment in the clinic?: IQ TALG Plasma Protein Binding Working Group  
    image Faraz Kazmi, Janssen Research & Development, Spring House, Pennsylvania, USA

    Derivation of Unbound Ki for Metabolic Enzymes: What have we learnt?
    Renu Singh, GSK, Phoenixville, Pennsylvania, USA

    Microphysiological Model to Investigate Ochratoxin A Nephrotoxicity 
    image Edward Kelly, University of Washington, Seattle, Washington, USA

    Kinetics and in vitro Challenges with AO
    image Kanika Choughule, Merck & Co., Inc., Boston, Massachusetts, USA

    Intestine Explant Barrier Chip: A Medium Throughput Microfluidic System to Study Drug Permeability and Host-microbe Interactions in ex vivo Intestinal Tissue
    imageJoanne Donkers, TNO, Zeist, The Netherlands

    Panel Discussion with All Speakers 

  • Session 2: Biological, Experimental and Methodological Challenges Associated with the Study of Drug Transporters
    Contains 7 Component(s)

    The sessions will cover laboratory and analytical challenges associated with studying enzymes and transporters in vitro, as well as challenges and potential solutions/best practices in translation of in vitro ADMET data to in vivo drug disposition and clinical drug-drug interactions (DDIs).

    Chairs: Aleksandra Galetin, University of Manchester, Manchester, England, United Kingdom and Laurent Salphati, Genentech Inc., South San Francisco, California, USA

    Critical in vitro Factors to Consider when Conducting IVIVE of Transporter-based Drug Disposition 
    image Jashvant Unadkat, University of Washington, Seattle, Washington, USA

    Challenges in Translation of in vitro Transporter Data to Predict Unbound Tissue Concentrations
    image Xiaoyan Chu, Merck & Co., Inc., Rahway, New Jersey, USA

    Challenges in Pharma Industry using in vitro and Preclinical Systems to Predict in vivo Clearance of Transporter Substrates 
    image Yurong Lai, Gilead Sciences, Foster City, California, USA

    Investigations of Compounds Elimination Through Direct Transporter-Mediated Intestinal Secretion 
    Laurent Salphati, Genentech Inc., South San Francisco, California, USA

    The Effect of Plasma Protein on Hepatic Drug Clearance in vitro and its Implications for IVIVE 
    Laura Francis, The University of Manchester, Manchester, United Kingdom

    Is the protein-mediated transport effect an artifact or a real phenomenon?
    Mengyue Yin, University of Washington, Seattle, Washington, USA

    A Novel in vitro Tool for Testing Drug Interactions of Human MDR3 Transporter
    Zsuzsanna Gaborik, SOLVO Biotechnology, a Charles River Company, Budapest, Hungary 

    Panel Discussion with All Speakers

  • Session 3: Using in vitro Enzyme and Transporter Data in Translational Models of Human Pharmacokinetics, Dose and DDI
    Contains 7 Component(s)

    The sessions will cover laboratory and analytical challenges associated with studying enzymes and transporters in vitro, as well as challenges and potential solutions/best practices in translation of in vitro ADMET data to in vivo drug disposition and clinical drug-drug interactions (DDIs).

    Chairs: Jashvant Unadkat, University of Washington, Seattle, Washington, USA and Kimio Tohyama, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, USA

    Translation of in vitro and in silico ADME Data to Guide Drug Discovery and Development
    image Marcel Hop, Genentech Inc., South San Francisco, California, USA

    PBPK Modelling and Simulation of Transporter-mediated PK and DDIs – Current Status and Challenges 
    image Aleksandra Galetin, University of Manchester, Manchester, England, United Kingdom

    Application of PBPK using a Matrix Qualification Approach for Translational Predictions of OAT1/OAT3 Inhibition in the Clinic by Cabotegravir 
    image Kunal Taskar, GSK, United Kingdom

    IVIVE of Transporter-Mediated Renal Clearance: Relative Expression Factor (REF) vs Relative Activity Factor (RAF) Approach
    Aditya Kumar, Department of Pharmaceutics, University of Washington, Seattle, Washington, USA

    Successes and Challenges Faced by Industry in IVIVE of Transporter-based Drug Disposition and DDIs
    image Manthena Varma, Pfizer, Niantic, Connecticut, USA

    IVIVE of Biliary Clearance of Rosuvastatin: a Comparison of the Proteomics-informed REF Approach vs. Sandwich-Cultured Human Hepatocytes (SCHH)
    image Flavia Storelli, University of Washington, Seattle, Washington

    Validation of PXB Chimeric Mice to Predict Human Liver-to-Plasma Kpuu of OATP1B1 Substrates
    image Bo Feng, Vertex Pharmaceuticals, Boston, Massachusetts, United States

    Panel Discussion with All Speakers

  • Session 4: Using in vitro Enzyme and Transporter Data in the Prediction of Drug-drug Interactions
    Contains 8 Component(s)

    The sessions will cover laboratory and analytical challenges associated with studying enzymes and transporters in vitro, as well as challenges and potential solutions/best practices in translation of in vitro ADMET data to in vivo drug disposition and clinical drug-drug interactions (DDIs).

    Chairs: Lei Zhang, US Food and Drug Administration, Silver Spring, Maryland, USA and Yurong Lai, Gilead Sciences, Foster City, California, USA

    Approaches and Recommendations by the IQ Induction Working Group for the in vitro Conduct and Analysis of Cytochrome P450 (CYP) Induction for the Assessment of Human Drug-drug Interaction   
    Niresh Hariparsad, AstraZeneca, Boston, Massachusetts, USA

    Industry Perspectives on Regulatory Guidance on Drug-drug Interactions  
    image Venkatesh Pilla Reddy, AstraZeneca, Cambridge, United Kingdom

    EMA Perspectives on Regulatory Guidance on Drug-drug Interactions 
    Elin Lindhagen, Medical Products Agency, Uppsala, Sweden

    FDA Perspectives on Regulatory Guidance on Drug-drug Interactions 
    image Xinning Yang, US Food and Drug Administration, Silver Spring, Maryland, USA

    Application of Transporter Biomarkers to DDI Risk Assessment
    image Hiroyuki Kusuhara, University of Tokyo, Tokyo, Japan

    PBPK Modeling of Concomitant CYP3A Auto-induction and Time-dependent Inhibition of the Pharmacokinetics of the CYP3A Substrate Aprepitant 
    image Tamara Cabalu, Merck & Co., Inc., Philadelphia, Pennsylvania, USA

    Predictive in vitro in vivo Extrapolation for Time Dependent Inhibition Of CYP1A2, CYP2C8, CYP2C9, CYP2C19 AND CYP2D6 Using Pooled Human Hepatocytes and a Simple Mechanistic Static Model
    Diane Ramsden, Takeda, Cambridge, Massachusetts, USA

    Panel Discussion with All Speakers