DDI 2019-Program

DDI-2019

22nd International Conference on Drug-Drug Interactions

 

Organizing Chair:
Albert P. Li, APSciences/In Vitro ADMET Laboratories, Inc.

Session Chairs:
Jingjing Yu, University of Washington
Lei Zhang, US FDA
Justin Lutz, Gilead Sciences, Inc.
Manthena Varma, Pfizer Inc.
Jialin Mao, Genentech
Bhagwat Prasad, University of Washington
Kim Brouwer, University of North Carolina, Chapel Hill
Kenneth Brouwer, BioIVT

DDI-2019:  22nd International Conference on Drug-Drug Interactions

 

THURSDAY, JUNE 20, 2019: DDI-2019 – DAY 1

 7:00 AM – 8:00 AM – REGISTRATION

 

8:00 AM – 8:15 AM

Welcome Remarks: Albert P. Li, APSciences/IVAL

 

8:15 AM – 8:45 AM

Opening Remarks: DDI Hot Topics (Ken Thummel, University of Washington; Seattle, WA)

 

Session 1: 2018 DDI Review: (Chair:  Jingjing Yu)

 

8:50 AM – 9:20 AM

OATP1B Inhibition: A comprehensive Review of the Clinical and Preclinical Interaction Data (Savannah McFeely, University of Washington; Seattle, WA) In recent years, the impact of the OATP1B transporters on drug-drug interactions (DDIs) has become a focus of research, and the evaluation of their role in drug disposition is recommended by regulatory agencies worldwide. While inhibitors of OATP1B1/1B3 have been identified in the literature and probe drugs have been proposed by some regulatory agencies, there is no general consensus on the ideal compounds to be used for clinical DDI studies. The aim of our work was twofold: to provide a thorough analysis of the available in vitro and in vivo data regarding OATP1B1/1B3 inhibitors and, from the identified compounds, propose the most selective as potential clinical tools.

 

9:20 AM – 9:50 AM

Review of the 2018-2019 Literature on Drug Interactions (Sophie Argon, University of Washington; Seattle, WA) Critical Review of the literature: 2018 drug-drug interactions publications reviewed and analyzed with particular focus on drug-enzymes and drug-transporter DDIs. A case study of clinically noteworthy drug-drug-interaction and gene-drug interaction will also be presented.

 

9:50 AM – 10:20 AM – BREAK

 

10:25 AM – 10:55 AM

Mechanistic analysis of pharmacokinetic DDIs and clinical relevance with drugs approved by the FDA in 2018 (Jingjing Yu, University of Washington, Seattle, WA)

 

10:55 AM – 11:25 AM – SESSION 1 PANEL DISCUSSION

 

11:25 AM – 1:30 PM – LUNCH

 

Session 2:  Regulatory Issues (Chair: Lei Zhang)

 

1:35 PM – 2:05 PM

Physiologically Based Pharmacokinetic Model Predictions of Ivosidenib as a Victim and Perpetrator of Drug-Drug Interactions: An industrial perspective (Chandra Prakash, Agios Pharmaceuticals, Inc.; Cambridge, MA)

 

2:05 PM – 2:35 PM

The use of induction slope vs measured Emax and EC50 in PBPK modeling in regulatory submission (Theunis Goosen, Pfizer Inc.; Groton, CT)

 

3:05 PM – 3:35 PM

Drug-Drug Interactions and Generic Drugs (Lei Zhang, US FDA; Silver Spring, MD) (Invited)

 

3:35 PM – 4:05 PM – BREAK

 

4:05 PM – 4:35 PM

Clinical Natural Product-Drug Interactions: Harvesting Precipitants and Mechanisms (Mary Paine, Washington State University; Spokane, WA) Sales of botanical and other natural products (NPs) continue to rise, increasing the risk for adverse interactions with conventional drugs. However, unlike for drug-drug interactions, rigorous guidelines for assessing potential clinically relevant NP-drug interactions are lacking. The National Center for Complementary and Integrative Health established the Center of Excellence for Natural Product-Drug Interaction Research in September 2015. A key deliverable of the Center is a set of recommended approaches to guide researchers in the proper conduct of NP-drug interaction studies. These approaches should lead to improved design of future NP-drug interaction research and ultimately, improved decisions regarding the optimal management of these complex interactions.

 

4:35 PM – 5:05 PM – SESSION 2 PANEL DISCUSSION

 

END OF DAY 1

 

FRIDAY, JUNE 21, 2019: DDI-2019 – Day 2

 

7:00 AM – 8:00 AM – REGISTRATION

 

Session 3: Enzyme and Transporter Induction (Chair:  Justin Lutz)

 

8:05 AM – 8:35 AM

Drug Transporter Induction: Can We Leverage P450 Data to Streamline Our Clinical Pharmacology Programs? (Justin Lutz, Gilead Sciences, Inc.; Foster City, CA)

 

8:35 AM – 9:05 AM

Characterization of CYP2C Induction in Cryopreserved Human Hepatocytes and Its Application in the Prediction of the Clinical Consequences of the Induction (Mika Nagai, Kaken Pharmaceutical Co., LTD.; Kyoto, Japan) It is important to estimate and reduce the drug-drug interaction (DDI) risk in the lead optimization stage of drug discovery. In this presentation, the new in silico methods for the prediction of CYP3A4, CYP2B6, CYP2C induction, recently established by us, and their application to drug development and the prediction of the clinical consequences of the CYP2C9 induction will be introduced.

 

 9:05 AM – 9:35 AM 

OATP Transporters are not induced by PXR Activator Rifampin: In Vitro and In Vivo Investigation (Congrong Niu, Gilead Sciences, Inc.; Foster City, CA) Membrane transporters play a pivotal role in drug absorption, disposition, metabolism and elimination.  While it is well-documented that both CYP3A and efflux transporter P-gp expressions are regulated through the activation of PXR and other nuclear receptors, controversial results exist in literatures for SLC uptake transporters such as OATP. The presentation will provide the overview of transporter gene regulations and update the audience in vitro and in vivo gene regulation data for clinically relevant uptake transporters.

 

9:35 AM – 10:05 AM

Observations and Recommendations Related to In Vitro and Clinical CYP3A Induction Variability and Risk Assessment from the IQ Induction Working Group (Diane Ramsden, Alnylam Pharmaceuticals; Cambridge, MA)

 

10:05 AM  – 10:35 AM – BREAK

 

10:35 AM – 11:05 AM – SESSION 3 PANEL DISCUSSION

 

 Session 4: In Vivo Preclinical and Clinical Approaches (Chair: Manthena Varma)

 

11:05 AM – 11:35 AM

Utility of Cynomolgus Monkey in characterizing transporter-mediated disposition and DDIs. (Manthena Varma, Pfizer; Groton, CT)

 

11:35 AM – 12:05 PM

Clinically Relevant Probe Drugs for Transporter DDI Evaluation: Perspectives from the International Transporter Consortium (ITC) (Xiaoyan Chu, Merck; Kenilworth, NJ)

 

12:05 PM – 2:00 PM – LUNCH BREAK

 

2:05 PM – 2:35 PM

Pheophorbide A: Fluorescent Bcrp Substrate to Measure Oral Drug-Drug Interactions in Real-Time In Vivo (Erin Schuetz, St Jude Children’s Research Hospital; Memphis, TN)

 

 2:35 PM – 3:05 PM

Proteomics-informed predictions of tissue concentrations of drugs and subsequent verification through PET imaging (Jashvant D. Unadkat, University of Washington; Seattle, WA)

 

3:05 PM – 3:35 PM – SESSION 4 PANEL DISCUSSION

 

3:35 PM – 4:05 PM – BREAK

 

Session 5: In vitro-in vivo extrapolation (Chair: Jialin Mao)

 

4:05 PM – 4:35 PM

Accurate estimation of drug exposure variability due to drug-drug interactions using fm,cyp derived from human hepatocytes (Bo Lindmark, AstraZeneca; Gothenburg, Sweden)

 

4:35 PM – 5:05 PM

Impact  of intracellular binding proteins on oxidative metabolism and clearance predictions (Nina Isoherranen, University of Washington; Seattle, WA)

 

5:05 PM – 5:35 PM

Towards Prospective Pharmacokinetic Prediction of OATP Substrates (Jialin Mao, Genentech; South San Francisco, CA)

 

5:35 PM – 6:05 PM

Protein Binding, Drug Transport and Drug Metabolism (Leslie Z. Benet, University of California San Francisco; San Francisco, CA)

 

 6:05 PM – 6:35 PM – SESSION 5 PANEL DISCUSSION

 

 

END OF DAY 2

 

SATURDAY, JUNE 22, 2019: DDI-2019 – Day 3

 

7:00 AM – 8:00 AM – REGISTRATION

 

Session 6: Hepatic versus Extrahepatic DDI (Chair: Bhagwat Prasad)

 

8:05 AM – 8:35 AM

A comparison of human hepatic and enteric drug metabolizing enzyme activities (Albert P. Li, In Vitro ADMET Laboratories LLC; Columbia, MD)

 

8:35 AM – 9:05 AM

Quantitative characterization of UDP-glucuronosyltransferases in human liver, intestine, kidney, lung and heart (Bhagwat Prasad, University of Washington; Seattle, WA)

 

9:05 AM – 9:35 AM

Hepatic and Renal Efflux Transporters in Drug Interactions and Toxicity (Yan Zhang, Ph.D., Incyte Corporation; Wilmington, DE) Efflux transporters play an important role in the absorption, distribution and elimination of therapeutic agents and their metabolites. Interruption of the transporter activity may alter the systemic pharmacokinetics and tissue exposure of target drugs, therefore, can potentially lead to organ toxicities. In this presentation, examples of efflux transporter mediated DDI in the liver and kidney will be discussed.

 

9:35 AM- 10:05 AM – BREAK

 

10:05 AM – 10:35 AM – SESSION 6 PANEL DISCUSSION

 

Session 7: Drug Induced Liver Injury (DILI) (Chairs: Kenneth Brouwer and Kim Brouwer)

 

10:35 AM – 11:05 AM

Clinical and Mechanistic Evidence for Associations between Drug-Transporter Interactions and DILI: BSEP and Beyond (Kim Brouwer, University of North Carolina at Chapel Hill; Chapel Hill, NC)

 

11:05 AM – 11:35 AM

Evaluation of BSEP Inhibition and Compensatory Mechanisms in Drug Development (Kenneth Brouwer, BioIVT; Durham, NC)

 

11:35 AM – 12:05 AM

Identification of DILI drugs based on Cytotoxic Reactive Metabolite Formation (Albert P. Li, In Vitro ADMET Laboratories LLC; Columbia, MD)

 

12:05 PM – 12:35 PM – SESSION 7 PANEL DISCUSSION

 

12:35 PM – 1:05 PM FINAL REMARKS – Albert P. Li, IVAL

 

 

END OF DAY 3

 

END OF CONFERENCE