Bringing Practical Applications of Endogenous Biomarkers for Drug Transporters a Step Closer: Current Status and Future Perspectives

Friday, March 1, 2024
10:00 am - 2:00 pm ET (US)

Session 3: Methods for Transporter Biomarker Identification, Liquid Biopsy, and Emerging Biomarkers of Efflux Transporters
Co-Chairs: Bhagwat Prasad, Washington State University, Spokane, Washington, USA & Pei Feng Shawn Tan, University of Manchester, Manchester, UK

10:00 am - 10:05 am | Welcome and Introductions

10:05 am - 10:40 am | Use of Metabolomics for Biomarker Identification and Validation
Martin Fromm, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlagen, Germany

Abstract: Transporter-mediated drug-drug interactions affect disposition and effects of multiple drugs. For drug approval, regulatory authorities require detailed information on inhibition of drug transporters by new molecular entities. Endogenous molecules are intensively discussed as tools for in vivo transporter drug-drug interaction evaluation. Metabolomics is a powerful tool for further characterization of previously proposed biomarkers and for the identification of novel biomarkers of transporter-mediated drug-drug interactions. Data will be discussed of a metabolomic analysis of sensitivity and specificity of 23 previously proposed biomarkers for renal transporter-mediated drug-drug interactions. These data highlight the need for focusing not only on sensitivity of putative biomarkers, but also consider the specificity of the respective biomarkers towards classical inhibitors of drug transporters.

About the Speaker: Martin F. Fromm is Director of the Institute of Experimental and Clinical Pharmacology and Toxicology and Chair of Clinical Pharmacology and Clinical Toxicology at the Friedrich-Alexander-University Erlangen-Nuremberg (Germany). He studied medicine and received his doctoral degree at the Friedrich-Alexander-University Erlangen-Nuremberg. He was a postdoctoral fellow at the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (Stuttgart, Germany) and at the Division of Clinical Pharmacology at Vanderbilt University (Nashville, TN). His research interests are drug transporters, biomarkers, drug metabolism, drug-drug interactions and medication safety. He has published more than 230 articles.

10:40 am - 11:15 am | Isolation of Exosomes/extracellular Vesicles as Biomarkers of Transporter Expression/activity: Challenges, Methodology and Promise 
Brahim Achour, University of Rhode Island, Kingston, Rhode Island, USA

Abstract: Tailoring drug dosage regimens according to a patient’s characteristics and specific needs, or so-called precision dosing, has recently been reinvigorated by the availability of novel technologies for characterizing patients and wider acceptance of simulated clinical studies. The concept is most useful for patients from special and disease populations or those prone to polypharmacy. The bottleneck for wider application of model-informed precision dosing (MIPD) has been the lack of approaches capable of generating individual ‘systems’ data relevant to the patient’s drug elimination capacity, such as the abundance of hepatic transporters. The use of liquid biopsy derived biomarkers, as a minimally invasive alternative to tissue biopsy, opened new avenues for advancing MIPD. In addition to the technical aspects of the technology, this talk will focus on the practical application of liquid biopsy output with virtual twin models, exploring the potential of such approach to significantly reduce uncertainty related to variability in predictions of drug exposure with a view to enable design of refined dosage regimens.

About the Speaker: Brahim Achour is an assistant professor at the College of Pharmacy, University of Rhode Island, and a consultant for the Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester, with research interests in the areas of pharmacokinetics, liquid biopsy and precision dosing. Dr Achour completed a pharmacy degree at the University of Manchester (2007), PhD training at CAPKR (2013) and post-doctoral training at CAPKR (2014-2022).
Dr. Achour has co-authored several research articles and patents related to development and applications of liquid biopsy technology. Brahim has extensive experience in multi-‘omics’ with specific expertise in quantitative proteomics and transcriptomics applied to the investigation of drug metabolism and transport. Along with experimental work, Brahim has teaching and consultancy responsibilities for external and affiliated companies and institutions in relation to the use of systems data in PBPK and liquid biopsy applications.

11:15 am - 11:50 am | An Update to Existing SLC Biomarkers: Evaluation of the Selectivity of Several OATP1B Biomarkers Using a Relative Activity Factor Method
Xiaoyan Chu, Merck, Rahway, New Jersey, USA

Abstract: In recent years, significant advances have been made in identifying endogenous biomarkers for solute carrier (SLC) transporters, particularly hepatic organic anion transporting polypeptides (OATP1B). One of extensively characterized OATP1B biomarkers is coproporphyrin I (CPI), which has been applied to assess OATP1B-mediated DDIs early in drug development. Besides CPI, several sulfate and glucuronide conjugates of bile acids that demonstrated high sensitivity for OATP1B inhibition have been identified and evaluated clinically. This presentation aims to 1) Provide an update on the latest progress in the characterization of OATP1B biomarkers; 2) Introduce an in vitro relative activity factor (RAF) method to determine the selectivity of several OATP1B biomarkers, and their translation to predicting DDIs; 3) Discuss the potential utility of multiplex transporter biomarkers to improve DDI prediction.

About the Speaker: Dr. Xiaoyan Chu is a Senior Director in the Department of Pharmacokinetics, Dynamics, Metabolism, and Bioanalytics at Merck & Co., Inc. in West Point, PA, USA. She obtained her PhD from the Department of Molecular Pharmacokinetics at the Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan. After completing her post-doctoral research at the Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan., she joined the Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism at Merck & Co., Inc. As the leader for the Transporter Science Group, her main responsibilities are to develop transporter related research and operational strategies to support Merck’s discovery and development portfolio, and to evaluate and establish new technologies and approaches to study the role of transporters in pharmacokinetics, efficacy, and toxicity of drugs. She has authored over 80 peer-reviewed research papers, book chapters, and has been invited to speak at over 40 national/international scientific conferences. She is the member of the International Transport Consortium (ITC) and serves as the Chair of the ISSX Transporter Focus Group from 2019 to 2022. She is also a member of the Editorial Board of Drug Metabolism & Disposition (DMD) and serves on the Industry Advisory Board at the College of Pharmacy & Pharmaceutical Sciences, Washington State University.

11:50 am - 12:15 pm | Break

12:15 pm - 12:50 pm | Discovery and Validation of Riboflavin as A Surrogate Marker of Breast Cancer Resistance Protein (BCRP)

Hong Shen, Bristol Myers Squibb, Princeton, New Jersey, USA

Abstract: Advancement of endogenous biomarkers for drug transporters as a tool for assessing drug-drug interactions depends heavily on initial identification and follow-up validation. To identify endogenous biomarkers of BCRP, we applied metabolomic approaches to profile plasma from Bcrp and P-gp knockout mice. We focused on BCRP specific substrates and identified riboflavin, which was significantly elevated in the plasma of Bcrp single- and Bcrp/P-gp double- but not P-gp single-knockout mice. Dual BCRP/P-gp inhibitor elacridar caused a dose-dependent increase of the AUC of riboflavin in mice (1.51- and 1.93-fold increases by 30 and 150 mg/kg elacridar, respectively). In 3 cynomolgus monkeys, we observed approximately 1.7-fold increases in the riboflavin concentrations caused by ML753286 (10 mg/kg), which correlated well with the increase of sulfasalazine, a known BCRP probe in monkeys. The effects of BMS-986371, a potent in vitro inhibitor of BCRP (IC50 0.40 µM), on the pharmacokinetics of riboflavin was then examined in healthy male adults (N = 14) following oral administration of methotrexate (7.5 mg) and sulfasalazine (1,000 mg) alone or in combination with BMS-986371 (150 mg). Oral administration of BMS-986371 increased the AUCs of rosuvastatin and sulfasalazine to 1.38- and 1.51-fold, respectively, and significantly increased AUC(0-4h), AUC(0-24h), and Cmax of riboflavin by 1.25-, 1.14-, and 1.11-fold (P-values of 0.003, 0.009, and 0.025, respectively) compared to the methotrexate and sulfasalazine alone group. Overall, these data indicate that plasma riboflavin is a promising biomarker of BCRP that may offer a possibility to assess drug candidate as a BCRP modulator in early drug development.

About the Speaker: Dr. Hong Shen is a Scientific Director in the Drug Metabolism and Pharmacokinetics (DMPK) Department at Bristol Myers Squibb, where he researches drug transporter activities and provides preclinical DMPK support for multiple drug discovery and development programs. He received his Ph.D. in Pharmaceutical Sciences under the supervision of Dr. David Smith at University of Michigan. Dr. Shen was in the organizing committee for the AAPS Drug Transporter Focus Group from 2014 to 2018. He is currently a committee member of the International Transporter Consortium (ITC), ISSX Transporter Focus Group, International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Transporter Working Group, and IQ OATP1B Biomarker Working Group. He received the James Gillette Drug Metabolism and Pharmacokinetics Awards sponsored by the American Society for Pharmacology and Experimental Therapeutics (ASPET) in 2001, 2007, 2018, and 2023. He has over 90 research publications and book chapters. His research is focused on applying mechanism-based approaches for the quantitative translation of preclinical in vitro and in vivo data to clinical findings in order to broadly impact drug discovery and development processes involving drug transporters.

12:50 pm - 1:25 pm | Identification and Evaluation of Biomarkers for BCRP

Kathleen Giacomini, University of California San Francisco, San Francisco California, USA

Abstract: Breast Cancer Resistance Protein (BCRP) encoded by ABCG2 is an important drug transporter that plays a role in the pharmacokinetics and tissue specific distribution of many therapeutic drugs in the intestine, liver and blood brain barrier. Unlike many pharmacokinetic transporters, there are no specific and validated metabolomic biomarkers for BCRP. In this research presentation, I will describe the discovery and in vitro as well as clinical validation of potential biomarkers for BCRP. Discovery of potential BCRP biomarkers used publicly available genomewide association-metabolomic data and a common function variant of BCRP, rs2231142, which encodes a reduced function variant, Q141K of BCRP. In addition, we used published metabolomic data in Bcrp knockout mice. Following discovery and in vitro validation studies in BCRP expressing. cells, clinical studies with rosuvastatin and eltrombopag, a BCRP inhibitor, were performed. These studies showed a clear interaction between eltrombopag and rosuvastatin, consistent with inhibition of intestinal BCRP. Biomarkers including riboflavin (vitamin B2) and others were measured and will be described in my presentation.

About the Speaker: Kathy Giacomini, is the current Dean of the University of California, San Francisco School of Pharmacy. Of multi-ethnic ancestry, Kathy has been recognized for her commitment to diversity as the winner of the UCSF Martin Luther King Award at UCSF and by the UCSF United Filipinx Association. She is a world renowned scientist as a leader in the field of membrane transporters with a focus on genetic polymorphisms. She cloned, characterized and discovered the endogenous role of the human transporter, OCT1 (SLC22A1), and recently de-orphaned SLC22A10, SLC22A24 and SLC22A15, discovering physiologic and pharmacologic substrates of the transporters. Together with others, she co-founded the International Transporter Consortium and the Pharmacogenomics Global Research Network. She is the Co-Principal Investigator of the UCSF-Stanford Center of Excellence in Regulatory Sciences and Innovation, funded by the Food and Drug Administration. She has received numerous awards for her scientific accomplishments including an honorary doctorate degree from Uppsala University and is an elected member of the National Academy of Medicine.

1:25 pm - 1:55 pm | Roundtable Discussion with Speakers

Moderated by Bhagwat Prasad, Washington State University, Spokane, Washington, USA and Pei Feng Shawn Tan, University of Manchester, Manchester, UK

1:55 pm - 2:00 pm | Session and Workshop Closing Remarks

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