23rd International Conference on Drug-Drug Interactions:

DDI Literature and NDA Update; Clinical and Regulatory DDI; Drug Metabolism/Transport Interplay in DDI; Renal Transporter DDI; Novel DDI Approaches

June 16-18, 2020

Husky Union Building, University of Washington; 4001 NE Stevens Way, Seattle, WA 98195



Organizing Chair:

Albert P. Li, /In Vitro ADMET Laboratories, Inc.

Session Chairs:

Jingjing Yu, University of Washington

Diane Ramsden, Alnylam Pharmaceuticals

Emi Kimoto, Pfizer, Inc.

Yan Zhang, Incyte Corporation



23rd International Conference on Drug-Drug Interactions


TUESDAY, JUNE 16, 2020;  DDI-2020 – DAY 1


7:00 AM – 8:00 AM – REGISTRATION


8:00 AM – 8:15 AM

Welcome Remarks (Albert P. Li, /IVAL; Columbia, MD)


8:15 AM – 8:45 AM

Opening Remarks (Ken Thummel, University of Washington; Seattle, WA)


Session 1: DDI Literature and NDA Update (Chair:  Jingjing Yu)


8:45 AM – 9:15 AM

Review of pharmacokinetic drug-drug interactions with drugs approved by the US Food and Drug Administration in 2019. (Jingjing Yu, University of Washington, Seattle, WA) Drug-drug interaction data obtained from New Drug Application reviews with drugs approved by the US Food and Drug Administration in 2019 were systematically analyzed using a mechanistic and quantitative approach. Key findings including metabolism- and transporter-mediated in vitro and clinical studies were reviewed, and drug interactions with possible significant clinical relevance were identified.


9:15 AM – 9:45 AM

Assessing the Impact of Inhibitory Metabolites on DDI Risk Assessment Decisions (Claire Steinbronn, University of Washington; Seattle, WA) It is well recognized that metabolites have the potential to inhibit CYP450 enzymes independently or in addition to their respective parent drug. Therefore, identifying inhibitory metabolites during the drug development process of NCEs is critical to accurately predict the risk of clinical drug-drug interactions (DDI) and the need for further clinical evaluations. This retrospective review of all drugs approved by FDA between 2013 and 2018 evaluated the impact of metabolite testing, as per the current FDA framework on in vitro metabolite testing, on IVIVE predictions and decisions for in vivo studies.


9:45 AM – 10:15 AM – BREAK



10:15 AM – 10:45 AM

A systematic review of absorption-based drug-drug interactions in recent NDA reviews (Katie Owens, University of Washington, Seattle, WA) Absorption-based drug-drug interaction data obtained from New Drug Application reviews with drugs approved in the past few years by the US Food and Drug Administration were systematically analyzed using a mechanistic and quantitative approach. Both in vitro and clinical studies concerning pH-dependency, chelation/binding, and gastrointestinal motility were reviewed and drug interactions with significant clinical relevance were identified.


10:45 AM – 11:15 AM

Pharmacodynamic Drug Interactions for Drugs Approved by the FDA in 2019 (Sophie Chung, athenahealth; Watertown, MA) This presentation will focus on pharmacodynamic drug interactions included in the prescribing labels of drugs approved by the FDA in 2019. The clinical relevance of these interactions as well as their mechanisms (additive, antagonistic, etc.) will be discussed.




11:45 AM – 2:00 PM – LUNCH


Session 2:  Clinical and Regulatory DDI (Chair: Diana Ramsden)


2:00 PM – 2:30 PM

Factors Impacting Magnitude of Clinical DDI Due to Induction: Focus on CYP3A Substrates (Diane Ramsden, Alnylam Pharmaceuticals; Cambridge, Inc.; Cambridge, MA) A large set of clinical CYP3A induction data was collected to evaluate the utility of in vitro induction data to predict clinical effect.  Aggregate analysis of the clinical dataset demonstrated that even with the same inducer/substrate pair a large range of responses was observed.  This presentation will take the audience through potential contributors to this variability and highlight areas that may lead to improved extrapolation.


2:30 PM – 3:00 PM

Recommendations for the Design of Clinical Drug-Drug Interaction Studies with Itraconazole using a Mechanistic PBPK Model (Yuan Chen, Genentech; South San Francisco, CA) Regulatory agencies currently recommend itraconazole (ITZ) as a strong cytochrome P450 3A (CYP3A) inhibitor for clinical drug-drug interaction (DDI) studies. This work by an IQ (International Consortium for Innovation and Quality in Pharmaceutical Development) working group (WG) is to develop and verify a mechanistic ITZ PBPK model and provide recommendations for optimal DDI study design based on model simulations. To support model development and verification, in vitro and clinical PK data for ITZ and its metabolites were collected from WG member companies. The model predictions of ITZ DDIs with seven different CYP3A substrates were within the Guest criteria for 92% of AUC ratios and 95% of Cmax ratios, thus verifying the model for DDI predictions. The verified model was used to simulate various clinical DDI study scenarios considering formulation, duration of dosing, dose regimen, and food status to recommend the optimal design for maximal inhibitory effect by ITZ.



3:00 PM – 3:30 PM

PBPK upate at the US FDA (Yuching Yang, US FDA; Silver Spring, MD)


3:30 PM – 4:00 PM – BREAK


4:00 PM – 4:30 PM

In vivo probe substrates for transporter-mediated DDIs (Chih-hsuan Hsin, University Hospital Cologne (AöR); Köln, Germany) The clinical relevance of transporter-mediated DDIs (T-DDIs) is increasingly recognized. Because of the low specificity for substrates and inhibitors, prediction of T-DDIs from in vitro data is poor. In contrast, the application of the in vivo probe substrate approach, which has been established for drug metabolizing enzymes, may provide a more reliable basis for assessing T-DDIs. There are however specific challenges for quantifying the activity of individual transporters depending on the location of their expression.


4:30 PM – 5:00 PM

Mechanistic modeling approaches to simultaneously estimate fmCYP3A and FG of CYP3A substrates from clinical DDI data (Michael Gertz, Roche; Basel, Switzerland)


5:00 PM – 5:30 PM

A Comparison of Endogenous Molecules as Biomarkers of OATP1B Inhibition (Aleksandra Galetin, The University of Manchester; Manchester, UK) Endogenous biomarkers are increasingly considered as clinically relevant tools for the assessment of transporter function in vivo and corresponding drug-drug interactions (DDIs). The presentation provides an overview of potential OATP1B1 endogenous biomarkers; use of single vs. combination of biomarkers to de-risk OATP1B-mediated DDIs will be illustrated. Application of mechanistic modelling to support qualification of endogenous biomarkers will be presented, with a focus on coproporphyrin I (CPI). Minimal physiologically-based pharmacokinetic (PBPK) model for CPI incorporates the impact of OATP1B1 c.521T>C genotype on CPI plasma exposure and inter-individual variability in its baseline concentration. Importance of mechanistic biomarker models as translational tools to facilitate the design of clinical studies and evaluation of transporter-mediated DDI risk will be discussed.







DDI-2020 – DAY 2


7:00 AM – 8:00 AM – REGISTRATION


Session 3: Novel DDI Approaches (Chair: Albert P. Li)


8:00 AM – 8:30 AM

Expression of Drug Metabolizing Enzyme in Human Intestines (Stefan Oswald, University Medicine Greifswald; Greifswald, Germany) The oral bioavailability of many drugs on the market is strongly influenced by intestinal and hepatic biotransformation by cytochrome P450 (CYP450) enzymes and UDP-glucuronosyltransferases (UGT). In order to estimate their impact on drug disposition, data on their absolute intestinal and hepatic abundance are required. Though this intraindividual information was reported for very few CYP enzymes, a systematic description is not yet available. Hence, it was the aim of the current study to determine the absolute amount of clinically relevant CYP and UGT enzymes along the human intestine and in the liver from the same donors. Tissues were obtained from eight cadaveric healthy organ donors (3 females, 5 males; aged from 19 to 60 years) comprising one duodenal, two jejunal, one ileal, one colonic and one hepatic sample. After tissue disruption and homogenization, the whole tissue lysate was subjected to a tryptic digestion using the filter aided sample preparation (FASP) approach. A validated LC-MS/MS method has been applied for the simultaneous absolute quantification of nine CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) and four UGT enzymes (UGT1A1, UGT1A3, UGT2B7 and UGT2B15). Protein quantification has been conducted by targeted proteomics using enzyme specific tryptic peptides and stable isotope-labelled peptides as internal standard. In addition, the respective gene expression was determined using quantitative real-time PCR. Generally, all 13 enzymes could be quantified in hepatic tissues. In contrast, only five CYPs (CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5) as well as three UGT enzymes (UGT1A1, UGT1A3 and UGT2B7) could be found along the human intestine with lower quantities compared to the liver. Almost all of the enzymes expressed in the intestine showed the highest abundance in the jejunum, followed by duodenum, ileum and colon, which was in accordance with the gene expression data. For the first time, our study gives a comprehensive overview on the absolute intraindividual protein abundance of clinically relevant enzymes both along the human intestine and in the liver. The enzyme distribution was markedly different between the investigated intestinal sections, which may affect the intestinal drug absorption.


8:30 AM – 9:00 AM

A Comparison of In Vitro Enteric and Hepatic DDI Potential of Orally Administered Drugs (Albert P. Li, IVAL; Columbia, MD).  Drug-drug interactions of an orally administered drug is manifested firstly at the intestines, then, upon absorption into the portal circulation, in the liver.  As the drug concentration in the intestinal lumen is substantially higher than that in the plasma, P450 inhibitors deemed to have insignificant DDI potential with respect to hepatic metabolism may have substantial enteric DDI effects.  This hypothesis is examined in our laboratory via a comparison of in vitro hepatic and enteric P450 inhibitory potential of various orally administered drugs using hepatocytes and enterocytes as in vitro experimental systems for hepatic and enteric drug metabolism, respectively.


9:00 AM – 9:30 AM

Functions of microRNAs in drug metabolizing enzyme expression and drug-drug interactions (Dongying Li, US Food and Drug Administration-National Center for Toxicological Research; Jefferson, AR) Cytochrome P450 (CYP) metabolizing enzymes catalyze Phase I metabolic reactions, which may bioactivate or detoxify drugs, and the levels of CYP expression influence their biological effects.  MicroRNAs (miRNAs) are critical regulators of CYP expression and may exhibit altered expression in response to therapeutic drug exposure.  MiRNA-dependent regulation of CYP expression thus influences the metabolism of the drug itself and potentially other co-administered drugs, contributing to drug resistance or drug-drug interactions.


9:30 AM – 10:00 AM – BREAK


10:00 AM – 10:30 AM

Development of Metabolically Competent HepG2 Cells for Assessing Drug-induced Liver Injury and Drug-drug Interactions (Si Chen, National Center for Toxicological Research/FDA; Jefferson, AR) Genetic modification of HepG2 cells to increase the expression of the drug-metabolizing enzymes can overcome the low biotransformation capacity of HepG2 cells and improve their utility in toxicity testing and metabolism-associated drug-drug interactions investigation. Towards this goal, a battery of HepG2-derived stable cell lines that individually express 14 cytochrome P450s (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7) were developed. The applications of these cell lines in assessing drug-induced liver injury and drug-drug interactions were demonstrated in the studies of several FDA-regulated drugs.




11:00 AM – 2:00 PM – LUNCH



Session 4: Drug Metabolism/Transport Interplay in DDI (Chair:  Emi Kimoto)


2:00 PM – 2:30 PM

Mechanistic Evaluation of the Complex Drug-Drug Interactions (DDIs): Contribution of CYPs, P-gp and OATP1B1 (Emi Kimoto, Pfizer, Inc.; Groton, CT) Since understanding DDIs remains challenging as a major concern in drug discovery and development, emphasizing the need for projection of the potential impact in humans, especially quantitative prediction of complex DDIs, is important. The case example of maraviroc will be introduced to illustrate the projection of DDIs that involve transporter-enzyme interplay.



2:30 PM – 3:00 PM

Quantitative Prediction of Drug-Drug Interactions with Common Statin Co-meds: A framework for decision-making within Drug Discovery/Development (Hayley Atkinson, Cyprotex Discovery Ltd; Cheshire UK) Due to polypharmacy, drug-drug interactions (DDIs) continue to account for 5% of UK hospital admissions and as such remain a major regulatory concern.  This is particularly true for common co-meds such as statins which due to their prescribing prevalence in patients with co-morbidities have high potential for DDI.  Within Drug Discovery and Development we are moving away from relatively simple hazard identification of DDI potential using basic static equations detailed in regulatory guidance to actual risk analysis and mitigation using quantitative prediction of DDI.  Using mechanistic static equations we can predict the AUC change of each statin due to inhibition of its critical enzyme/transporter pathway(s) so that the clinical team can make a decision on whether any potential DDI is simply a pharmacokinetic DDI or a clinically significant DDI requiring intervention.  The statin mechanistic equation model requires very few in vitro input parameters and can be utilized towards aiding preclinical development candidate selection and towards reducing unexpected clinical findings in patients providing a useful tool in Drug Discovery and Early Development.


3:00 PM – 3:30 PM

Genetic Polymorphisms in OATP1B1: Effects on drug-drug interactions and associated biomarkers (Kathy Giacomini, UCSF; San Francisco, CA) Reduced function genetic polymorphisms can be used to discover naturally occurring substrates of transporters in the liver, kidney and intestine.  OATP1B1, a transporter abundantly expressed in the human liver, has a common reduced function polymorphism, OATP1B1-Val174Ala.  Here I describe using OATP1B1-Val174Ala to discover natural substrates of the transporter, which were then validated in OATP1B1 expressing cell lines.  Several of these endogenous OATP1B1 substrates were validated as biomarkers for OATP1B1-mediated drug-drug interactions in clinical drug-drug interaction studies.


3:30 PM – 4:00 PM – BREAK


4:00 PM – 4:30 PM

Mechanism based analysis of time-dependent inhibition of OATP1B and its impact on DDI prediction (Yuichi Sugiyama, Sugiyama Laboratory, RIKEN, Yokohama, Japan) OATP1B is involved in the hepatic uptake of various anionic drugs, and drug-drug interactions (DDIs) can be caused by OATP1B inhibition. Recent reports provided quantitative predictions for OATP1Bs-mediated DDIs between statins and cyclosporine A(CsA)/rifampicin (RIF) based on PBPK models (1). In the process of the analyses, the in vitro-in vivo discrepancies in the Ki values for OATPs were revealed. The underlying mechanisms are not fully understood, but substrate- and time-dependent inhibition of OATP1B1 are considered to account at least in part for the discrepancies (1,2).  Such discrepancies may hamper the practical use of PBPK modeling for DDI prediction via a bottom-up approach. To make a bottom-up prediction of OATP1Bs mediated DDI successful, pre-incubation time dependent Ki values should be kept in mind.  We now attempted to establish a comprehensive PBPK model to account for such in vitro-in vivo Ki difference (3).







DDI-2020 – Day 3

7:00 AM – 8:00 AM – REGISTRATION


Session 5: Renal Transporter DDI (Chair: Yan Zhang)


8:00 AM – 8:30 AM

Overview: Renal Transporter Mediated DDI (Yan Zhang, Nuvation Bio; New York, NY)


 8:30 AM – 9:00 AM

Renal Transporter Drug Interaction Risk Assessment Utilizing In Vitro and In Vivo Tools: Scientific and Industry Perspectives (Hong Shen, Bristol-Myers Squibb; Princeton, NJ) Understanding the involvement of transporters in renal disposition and drug-induced kidney injury has become an essential part of risk assessment in drug development because these transporters play an important role in drug distribution, excretion, and toxicity. These investigations often start with experiments using in vitro models to assess the transport and inhibition potentials of an investigational compound towards renal transporters. Data from numerous in vitro and in vivo tools such as animal models and endogenous biomarkers are integrated to predict drug interactions and inform about potential adverse effects. This presentation will focus on the utility of innovative approaches in translating the in vitro kinetic data to predict drug interactions and adverse effects involving renal transporters at BMS.


9:00 AM – 9:30 AM (Kathleen Hillgren)




10:00 AM – 10:30 AM – BREAK


10:30 PM – 11:00 NOON


(Chair:   Albert P. Li, IVAL)