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12Th International ISSX Meeting 28‒31 July 2019 Portland, Oregon

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12Th International ISSX Meeting 28‒31 July 2019 Portland, Oregon ABSTRACTS FROM THE 12TH INTERNATIONAL ISSX MEETING 28‒31 July 2019 Portland, Oregon, USA 12th International ISSX Meeting 28‒31 July 2019 Portland, Oregon, USA Contents Sunday, 28 July 2019 Short Course 1: Advances in the Role of Transporters in Drug Development 3 Abstracts: SC1.1 - SC1.5 Short Course 2: Non-P450 Enzymes in ADMET for Drug Discovery and Development 5 Abstracts: S2.1 - SC2.4 Short Course 3: State of the Art PKPD and QSP Modeling 6 Abstracts: SC3.1 - SC3.5 Short Course 4: Idiosyncratic Drug-induced Liver Injury 8 Abstracts: SC4.1 - SC4.4 Keynote Lecture: Model-Informed Precision Dosing at the Bedside: Scientific Challenges and Opportunities 10 Abstract: K1 Monday, 29 July 2019 Plenary Lecture 1: How Technology, Big Data and Systems Approaches are Transforming 21st Century Healthcare 10 Abstract: L1 Pre-doctoral/Graduate and Postdoctoral Poster Awards Finalist Poster Presentations 40 Abstracts: A1 - A12 Poster Presentation Session 1 47 Abstracts: P1 - P87 Parallel Symposium 1: Personalized Medicine: Use of Pharmacogenomics and Other Patient-specific Factors to Individualize Drug Dosing and Treatment 11 Abstracts: S1.1 - S1.4 Parallel Symposium 2: State of the Art for Organs on Chips 12 Abstracts: S2.1 - S2.4 Parallel Symposium 3: Quantitative Pharmacokinetic and Pharmacology Methods and Strategies in the Discovery and Development of Biotherapeutics 13 Abstracts: S3.1 - S3.4 Parallel Symposium 4: Microbiome-Environment-Drug Interactions: Emerging Tools and Applications 15 Abstracts: S4.1 - S4.4 Tuesday, 30 July 2019 Plenary Lecture 2: Evaluation of Disease Progression / Drug Effects by Expanding the PK Concept 16 Abstract: L2 Parallel Symposium 5: Disease Effect on Transporter Regulation and Function 17 Abstracts: S5.1 - S5.4 Parallel Symposium 6: Advances in the Study of Drug Metabolism 19 Abstracts: S6.1 - S6.4 Pre-doctoral/Graduate and Postdoctoral Poster Awards Finalist Poster Presentations 40 Abstracts: A1 - A12 Poster Presentation Session 2 90 Abstracts: P88 - P181 1 Parallel Symposium 7: Driving Asia-Inclusive Global Drug Development through Translational Science and Clinical Pharmacology: Towards Enhanced Benefit-Risk and Decreased Access Lag 20 Abstracts: S7.1 - S7.4 Parallel Symposium 8: State-of-the-Art Approaches in Drug Metabolizing Enzymes and Transporters (DMET) Biomarker Research: Path from Discovery to Validation 22 Abstracts: S8.1 - S8.4 Wednesday, 31 July 2019 Plenary Lecture 3: Drug Metabolism, Pharmacogenomics and the Quest to Personalize HIV Treatment and Prevention 23 Abstract: L3 Parallel Symposium 9: Role of Albumin in Drug Disposition Revisited 24 Abstracts: S9.1 - S9.3 Parallel Symposium 10: Ontogeny of Enzymes and Transporters and their Implications in Pediatric PBPK Modeling to Inform Pediatric Dosing 25 Abstracts: S10.1 - S10.4 Poster Presentation Session 3 134 Abstracts: P182 - P252 Symposium 11: ‘War Stories’ – ADME Issues Encountered and Addressed in Drug Discovery and Development 27 Abstracts: S11.1 - S11.4 Poster Details 29 Finalists for the Pre-doctoral/Graduate Poster Awards Competition (Monday, 29 July - Wednesday, 31 July 2019) 40 Abstracts: A1 - A6 Finalists for the Postdoctoral Poster Awards Competition (Monday, 29 July - Wednesday, 31 July 2019) 43 Abstracts: A7 - A12 Poster Presentations (Monday, 29 July - Wednesday, 31 July 2019) 47 Abstracts: P1 - P252 Author Index 171 Keyword Index 178 Notes Pages 179 2 12th International ISSX Meeting Speaker Abstracts SC1.1 - THE NEXT FRONTIER IN ADME RESEARCH: PREDICTING AND VERIFYING TISSUE DRUG CONCENTRATIONS USING A PROTEOMICS AND PET IMAGING APPROACH Jashvant D. Unadkat University of Washington, USA In the drug development process, predicting CYP metabolic clearance of drugs using recombinant and human liver microsomes (HLMs) has been relatively successful. However, for several reasons predicting non-CYP and transporter- based clearance of drugs remains a challenge. First, the rate-determining step in the clearance of a drug must be identified – is it metabolism or transport or both. If transport is rate-determining, using recombinant enzymes or HLMs for predicting the in vivo clearance of drugs (IVIVE) will not be successful. Vice-versa is also true, that is using transporter- expressing cell lines will not help predict metabolic clearance of drugs. If both processes are rate-determining, both need to be included in IVIVE. Second, quantification of transporters and non-CYP enzymes in various ADME tissues is needed. Such data are beginning to be available. For IVIVE of transporter-mediated clearance, the mechanism of transport, plasma membrane vs. intracellular expression of transporters, both in vitro and in vivo, should be considered. For example, the membrane potential difference, which drives OCT2 transport, appears to be different in cell lines vs. kidney epithelial cells. Third, significant challenges remain in predicting in vivo efflux transport activity, especially in the liver (e.g. MRP2) and kidneys. These challenges/gaps will be discussed. Supported by UWRAPT through funding from Biogen, Bristol-Myers Squibb, Gilead, Merck & Co., Genentech, Pfizer and Takeda. SC1.2 - ADVANCING PREDICTIONS OF TISSUE AND INTRACELLULAR DRUG CONCENTRATIONS USING IN VITRO AND PBPK MODELING APPROACHES Yingying Guo Eli Lilly and Company, USA Knowledge of unbound tissue drug concentrations is important to the understanding of efficacy, toxicity and drug-drug interactions especially for drugs with transporter-mediated drug disposition. This presentation will examine the state-of- the-art on predictions of tissue and intracellular drug concentrations based on the recent ITC3 whitepaper (1). Critical overview will be provided for the in vitro methods that determines intracellular and subcellular drug concentrations. Selected examples will be used to illustrate the utility of preclinical, clinical and pharmacodynamic data to support physiologically based pharmacokinetic (PBPK) modeling to understand disconnects between systemic and tissue drug exposure. Current best practices and practical strategies will also be discussed for selecting methods to estimate or predict tissue and intracellular concentrations and then apply to PBPK modeling for human pharmacokinetic, efficacy and safety assessment in drug development. Reference: 1. Guo Y, Chu X, Parrott NJ, Brouwer KLR, Hsu V, Nagar S, et al. Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches. Clinical Pharmacology and Therapeutics. 2018;104(5):865-89.. SC1.3 - INFLUENCE OF TRANSPORTER POLYMORPHISMS ON DRUG DISPOSITION AND RESPONSE: A PERSPECTIVE FROM THE INTERNATIONAL TRANSPORTER CONSORTIUM Sook Wah Yee University of California San Francisco, USA Membrane transporters are critical determinants of drug disposition, toxicity and response. They are becoming increasingly important in drug development both as drug targets and sites of clinical drug-drug interactions, DDIs. In this short course, I will focus on transporters in the Solute Carrier and ATP Binding Cassette Superfamilies, that have common and reduced function polymorphisms which are considered highly influenced to drug response and disposition by the International Transporter Consortium (see Clinical Pharmacology and Therapeutics, 104, 803-817, 2018). Examples will include highly important polymorphisms in OATP1B1 and BCRP, as well as OCT1, that was recently highlighted by the International Transporter Consortium as a transporter with important polymorphisms that should be considered in drug development programs. Finally, I will highlight commonly used databases for research relevant to membrane transporters. 3 12th International ISSX Meeting Speaker Abstracts SC1.4 - CAN BSEP INHIBITION TESTING IN DRUG DISCOVERY AND DEVELOPMENT REDUCE LIVER INJURY RISK? AN INTERNATIONAL TRANSPORTER CONSORTIUM PERSPECTIVE Gerry Kenna Safer Medicines Trust, United Kingdom The Bile Salt Export Pump (BSEP) is a protein located in the apical plasma membrane domain of hepatocytes, which mediates ATP-dependent vectorial efflux of bile acids into bile. Inhibition of BSEP activity has emerged as one of several important mechanisms by which idiosyncratic drug induced liver injury (DILI) may arise in humans, but not in the animal species used in nonclinical drug safety studies. Recently, the International Transporter Consortium (ITC) has recommended that proactive evaluation and understanding of BSEP inhibition can aid internal decision making on DILI risk in drug discovery and development and has provided pragmatic guidance on how this can be undertaken (see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220754). The objective is to reduce and manage DILI risk. The reasons for these recommendations will be presented. In addition the advantages and limitations of the available methods for assessment of BSEP inhibition, and evaluation of its potential adverse functional consequences, will be discussed. Most commonly, BSEP inhibition by drugs is evaluated in vitro using inverted membrane vesicles from insect cells transiently transfected with plasmid vectors that encode the protein. When interpreting the data provided by these and other in vitro methods, it is important to assess potency by determination of an IC50. When considering potential DILI risk, the in vitro BSEP IC50 value should be compared to the maximum total plasma drug concentration at steady state. Various follow up studies can further aid the interpretation of in vitro BSEP inhibition data and
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