DDI-2015
18th International Conference on Drug-Drug Interactions:
NDA and Literature Update; Novel DDI Experimental Approach: Human Hepatocytes Cultured in Human
Plasma; Physiologically-Mediated Drug Interactions; Transporters and IVIVE: Quantitative Proteomics to PET
Imaging Tissue Concentrations; Biotherapeutics Disposition & DDI
June 29 – July 1, 2015
Husky Union Building, University of Washington; Seattle, WA, USA
4001 NE Stevens Way, Seattle, WA 98195
(206) 543-8131
REGISTRATION DISCOUNT UNTIL MAY 29, 2015
ISC, INC.
9221 Rumsey Road, Suite # 8
Columbia, Maryland 21045 USA
DDI-2015 MEDIA PARTNER
Featuring the Following Experts: Albert P. Li; Ken Thummel; Chuang Lu; Yuichi Sugiyama; Jash Unadkat; Jan
Wahlstrom; Eugenia Kraynov; Isabelle Ragueneau-Majlessi; JIngjing Yu; Wen Lin; Joe Ware; Jialin Mao; Sophie Argon;
Stephen Wang; Maciej J. Zamek-Gliszczynski; Yang Xu; Ken-ichi Umehara; Yang Xu; Anup Zutshi
DDI-2015 is a yearly event providing a comprehensive update on the status of the science of drug-drug interactions and its
relevance to drug development. Presentations will be given by experts from industry and academia. Topics covered will include
literature and NDA reviews, mechanism and in vitro-in vivo extrapolation of DDI via enzyme and transporter inhibition and
induction. The conference will also include a review on the current status of DDI potential of biologics and industrial perspectives.
PLEASE VISIT US ONLINE AT WWW.IFSCOMM.ORG
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Organizing Chairs:
Albert P. Li, APSciences/In Vitro ADMET Laboratories, LLC
Isabelle Ragueneau-Majlessi, University of Washington
Jashvant Unadkat, University of Washington
Jan Wahlstrom, Amgen Inc.
Stephen Wang, Pfizer, Inc.
DDI-2015
18 International Conference on Drug-Drug
Interactions
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MONDAY, JUNE 29, 2015
DDI-2015 – DAY 1
8:00 AM – 9:00 AM – REGISTRATION
9:00 AM – 9:15 AM
Welcome Remarks: Albert P. Li, APSciences/IVAL
9:15 AM – 9:45 AM
Opening Remarks: Ken Thummel, University of
Washington; Seattle, WA
Session 1: NDA and Literature Update
(Chair: Isabelle Ragueneau-Majlessi)
9:45 AM – 10:30 AM
Critical Review of the 2014-2015 Literature (Sophie Argon,
University of Washington, Seattle, WA) 2014 and 2015 drugdrug interactions publications in 2014 and 2015 will be
reviewed and analyzed with particular focus on new findings on
drug-enzyme, drug-transporter interactions, and clinically
significant drug-drug interactions
10:30 AM – 11:00 AM – BREAK
11:00 AM – 11:45 AM
New Molecular Entities approved by FDA in 2014: review of
in vitro and in vivo DDI data (Jingjing Yu , University of
Washington; Seattle, WA) This presentation will focus on the in
vitro and clinical findings on drug-drug interactions of new drugs
approved by U.S. FDA in 2014.
11:45 PM – 2:00 PM – LUNCH BREAK
2:00 PM – 2:45 PM
Is BCRP Relevant to Human Drug PK, and What are the
Best Practices in Clinical BCRP DDI Study Design?: A
Literature
Review
(Maciej
J.
Zamek-Gliszczynski,
GlaxoSmithKline; Research Triangle Park, NC) BCRP limits
intestinal absorption of low-permeability substrate drugs and
mediates biliary excretion of drugs and metabolites. Based on
clinical evidence of BCRP-mediated drug-drug interactions
(DDIs) and the c.421C>A functional polymorphism affecting
drug efficacy and safety, both the FDA and EMA recommend
preclinical evaluation, and when appropriate, clinical evaluation
of BCRP-mediated DDIs. Although many BCRP substrates and
inhibitors have been identified in vitro, clinical translation has
been confounded by overlap with other transporters and
metabolic enzymes. Thus, mechanistic attribution of clinical
DDIs
to BCRP has been equivocal.
Regulatory
recommendations for BCRP-mediated clinical DDI studies are
challenging, as consensus is lacking on the choice of the most
robust and specific human BCRP substrates and inhibitors and
optimal study design. This presentation proposes a path
forward based on a comprehensive analysis of available
data. Oral sulfasalazine (1000 mg, IR tablet) is the best
available clinical substrate for intestinal BCRP, oral rosuvastatin
(20 mg) for both intestinal and hepatic BCRP, and intravenous
rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000
mg) and lapatinib (250 mg) are the best available clinical BCRP
inhibitors. To interrogate the worst-case clinical BCRP DDI
scenario, study subjects harboring the BCRP c.421C/C
reference genotype are recommended. In addition, if
sulfasalazine is selected as the substrate, subjects having the
rapid acetylator phenotype are recommended, whereas if
rosuvastatin is selected, subjects harboring the OATP1B1
c.521T/T reference genotype are recommended. A proof-ofconcept clinical study is being planned by a collaborative
consortium.
2:45 PM – 3:15 PM – SESSION 1 PANEL DISCUSSION
Session 2: Novel DDI Experimental Approach:
Human Hepatocytes Cultured in Human Plasma
(Chair: A.P. Li)
3:15 PM – 4:00 PM
Culture Hepatocytes in Human Plasma to Count the Free
Concentration of Drugs in Evaluation of Drug-drug
Interactions (Chuang Lu, Takeda; Cambridge, MA)
Determination of free fraction of a drug (fu) in plasma and in an
in vitro test system (fu, mic) are essential for evaluation and
prediction of drug-drug interactions. However, accurate
determination of those values is often test system dependent.
This is especially challenge for high bound compounds. In this
presentation, a hepatocyte culture method using suspension of
human hepatocytes in human plasma will be presented. In this
system, determination of the free fraction can be avoided.
Further, in the present of an inhibitor for DDI evaluation, the
CYP activity remaining in this system can be extrapolated to the
[I]/ki ratio which is an important factor for prediction of drugdrug interaction.
4:00 PM – 4:45 PM
Human Hepatocytes Suspended in Human Plasma:
Application in Clearance Prediction and Drug-Drug
Interactions
(DDI)
Prediction
Involved
Inhibitory
Metabolites (Jialin Mao, Genentech, A Member of the Roche;
South San Francisco, CA) Prediction of human hepatic
clearance with in vitro metabolism assays is important in drug
discovery and development. Meanwhile, as recent EMA (final)
and FDA (draft) drug interaction guidances proposed that
human circulating metabolites should be investigated in vitro for
their drug-drug interaction (DDI) potential if present at ≥ 25% of
parent AUC (FDA) or ≥ 25% parent and ≥10% of total drugrelated AUC (EMA), more attention has been paid to how the
inhibitory metabolite(s) can be identified earlier in the drug
discovery and development. Therefore, cryopreserved human
hepatocytes suspended in human plasma has been explored
as one of the in vitro systems to predict human hepatic
clearance and DDIs involved the inhibitory metabolite. The
findings will be reviewed and discussed in details.
4:45 PM – 5:15 PM – BREAK
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5:15 PM – 6:00 PM
Long Term Culturing of Human Hepatocytes in Human
Plasma for DDI Studies (Albert Li, In Vitro ADMET
Laboratories, LLC; Columbia, MD) Extrapolation of in vitro DDI
results to clinical effects is complicated by plasma protein
binding that occurs in vivo but often is lacking during in vitro
experimentation. Adjustment of results based on fraction
unbound (fu) does not always lead to accurate prediction of in
vivo effects. In this study, human hepatocytes are cultured for
multiple days in human plasma.
The properties of the
hepatocytes after prolonged culturing and the application of the
human hepatocyte/human plasma cultures in DDI studies will
be discussed.
Transient Versus Chronic Cytokine Elevation (Yang Xu,
Amgen; Thousand Oaks, CA) Immunotherapy is an emerging
area of cancer treatment. Transient cytokine elevation was
observed during treatment of bispecific T-cell engager antibody
constructs as an initial immune response. The presentation will
discuss the potential DDI mediated by the transient cytokine
elevation and quantification of the DDI risk with a PBPK model.
The results will be compared with the DDI mediated by
inflammation based chronic cytokine elevation. The key
determinants of cytokine mediated DDI and its clinical
implication will be presented.
6:00 PM – 6:30 PM – SESSION 2 PANEL DISCUSSION
2:30 PM – 3:00 PM – SESSION 3 PANEL DISCUSSION
12:30 PM – 2:30 PM – LUNCH BREAK
END OF DAY 1
Session 4: Transporters and IVIVE: Quantitative
Proteomics to PET Imaging Tissue Concentrations
(Chair: Jashvant Unadkat )
TUESDAY, JUNE 30, 2015
DDI-2015 - Day 2
8:00 AM – 9:00 AM – REGISTRATION
Session 3: Physiologically-Mediated Drug
Interactions
(Chair: Jan Wahlstrom)
9:00 AM – 9:45 AM
Physiology, Biopharmaceutics and PharmacodynamicsMediated DDIs (Jan Wahlstrom, Amgen, Thousand Oaks, CA)
Physicochemical and biopharmaceutic properties may markedly
impact drug formulation and exposure. These properties may
also indicate susceptibility to drug interactions due to diseasebased changes in physiology or pharmacodynamics. This talk
will cover case examples outlining the potential for drug
interactions based on fundamental drug properties.
9:45 AM – 10:30 AM
Predicting Food Effects and Bioavailability Using
Preclinical
Models
with
Physiologically
Based
Pharmacokinetics (PBPK) Modeling (Wen Lin, Tycho
Heimbach, Jin Zhang, Fan Wu, Handan He, DMPK; Novartis
Institutes for Biomedical Research; East Hanover, NJ)
Physiologically based pharmacokinetic (PBPK) models are now
routinely employed at Novartis and the Industry (e.g.
http://www.orbitoproject.eu/) to provide quantitative, integrated
analyses of drug absorption, bioavailability and disposition both
in preclinical species and humans. Case studies demonstrating
PBPK impacts from early through late development will be
shared covering topics such as e.g.: a) PBPK modelling for
BCSII/IV drugs to predict human absorption and bioavailability,
b) food effect assessments across BCS/BDDCS classes, c)
anticipating negative food effects, d) trouble-shooting and using
parameter sensitivity analyses for poorly soluble drugs, e)
regional absorption studies for formulation and modified release
assessments
10:30 AM – 11:00 - BREAK
11:00 AM – 11:45 AM
Joe Ware, Genentech-TBD
11:45 AM – 12:30 PM
Cytokine Mediated DDI:
Perspectives
on
Impact
of
3:00 PM – 3:45 PM
Predicting Transporter-Based Drug Disposition and DDI
using Quantitative Proteomics: Methodological Issue and
Challenges (Jashvant (Jash) D. Unadkat, Department of
Pharmaceutics, University of Washington, Seattle, WA) The
next frontier in drug disposition is predicting transporter-based
drug disposition (including tissue concentrations) and DDI.
This is now becoming possible as data on transporter protein
expression are available through proteomics by quantifying
surrogate peptides using LC-MS/MS. However, like any other
approach, this approach to quantify transporter protein
expression has its limitations. My presentation will discuss
these limitations and methods to either overcome or avoid
these limitations. Supported by UWRAPT which is sponsored
by Genentech, Merck and Biogen Idec.
3:45 PM – 4:30 PM
Predicting Human Hepatic Clearance from In Vitro
Metabolism and Transport Data (Ken-ichi Umehara, Birk
Poller, Annett Kunze, Gian Camenisch; Novartis Institutes of
BioMedical Research (NIBR); Novartis Pharma AG; Basel,
SWITZERLAND) Membrane transporters and metabolism are
major determinants of the hepatobiliary elimination of drugs.
The presentation will give answer to the question which drugs
demonstrate transporter-based clearance in the clinic, based on
the in vitro data measured using human liver microsomes and
hepatocytes. Considering all four physiological processes
driving hepatic drug elimination (sinusoidal influx and efflux,
metabolism and biliary secretion), a mechanism-based
hepatobiliary clearance prediction model will be presented
determining the individual intrinsic clearance for compounds
with various physicochemical and pharmacokinetic properties.
Furthermore, analysis of the contribution of the individual
uptake transporters to total hepatic uptake will be presented.
4:30 PM – 5:00 PM – BREAK
5:00 PM – 5:45 PM
Imaging Hepatic Concentration and Biliary Excretion of
Drugs (Yuichi Sugiyama, Sugiyama Laboratory, RIKEN
Innovation Center, RIKEN, Yokohama, Japan) PET is a
promising approach to determine the functional change of
transporters associated with genetic polymorphisms or drugdrug interactions. Labeled PET probes are being developed for
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specific transporters. For example, the effects of changes in
uptake and efflux transporters activity on systemic and hepatic
exposure of statins were determined. Here in this presentation,
I will share will you our recent progress in the use of the
analysis of plasma clearance of drugs and PET imaging to
evaluate the transporter function in vivo including PET probes
for hepatic uptake transporters (OATP1B1, OATP1B3) and
biliary excretion transporters (MRP2, BCRP)) both in
experimental animals and in human.
About Institute for Scientific Communications, Inc.
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knowledge via effective communications. ISC sponsors
conferences and workshops to allow exchange of scientific
observations and ideas, with the ultimate goal being timely
application of the latest scientific discoveries to better
human lives. Please visit our web site at www.ifscomm.org.
5:45 PM – 6:15 PM – SESSION 4 PANEL DISCUSSION
POSTER PRESENTATIONS:
WEDNESDAY, JULY 1, 2015
DDI-2015 - Day 3
8:00 AM – 9:00 AM – REGISTRATION
SESSION 5: Biotherapeutics Disposition & DDI
(Chair: Stephen Wang)
9:00 AM – 9:45 AM
Recommendations from the IQ-sponsored ADC ADME
Working Group on the Strategy for Assessing DDI of
Antibody-Drug Conjugates (Eugenia Kranov, Pfizer, Inc.; La
Jolla, CA) This presentation will discuss recommended strategy
for assessing DDI potential of Antibody-Drug Conjugates
generated by a cross-company working group . The talk will
address selection as well as pros and cons of available
experimental systems, translation of preclinical results to the
clinical situation, and clinical implications.
9:45 AM – 10:30 AM
(Stephen Wang, Pfizer, Inc.; Cambridge, MA)-TBD
10:30 AM – 11:00 AM
11:00 AM – 11:45 AM
Site-of-Action Models: A Systems Modeling Approach to
Quantifying
Pharmacology
(Anup
Zutshi.,
Pfizer
Andover/Cambridge Laboratories; Cambridge) The basic tenets
of establishing pharmacology require that 1) the drug gets to
the site-of-action, following which 2) the drug binds to its
intended target with high affinity and the binding 3) results in
the anticipated effects for which the drug was intended and
designed. Using a combination of pharmacokinetic and
equilibrium binding models called ‘Site-of-Action’ models, we
have attempted to quantitatively understand the drug related as
well as the physiological system related factors that impact the
desired pharmacological outcomes. Case studies will be
presented to depict the impact of this approach to decision
making in early discovery.
11:45 AM – 12:15 PM – FINAL REMARKS – ALBERT P. LI
(IVAL)
Poster Presentations are always encouraged.
Please
submit your poster abstract for approval by the organizing
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board by May 30 . Poster size should be no larger than 3
feet high by 6 feet long. Abstracts of posters will be
included in the conference materials and will be available
on the ISC website. The conference materials will be
posted on the basis of availability from the author or
presenter.
There is no formal poster presentation
scheduled. All posters will remain displayed throughout
the conference. Please be prepared to display your poster
th
during registration on Sunday, June 28
or before the
th
first session begins on Monday, June 29 .
Poster
presenters will have ample time for discussion during
breaks and Panel discussions. Submit posters abstracts
for approval to Nola Mahaney, ISC; 9221 Rumsey Road,
Suite # 8; Columbia, MD 21045 or email files attachment to
[email protected]. Approved poster applicants are
responsible for completing a conference attendance
registration form and payment of fee - visit
www.ifscomm.org
- and for the shipping of the poster
itself. Please contact Nola Mahaney for any questions or
comments. Please refer to “Travel Information” for hotel
address and shipping information.
The conference will be held at
Husky Union Building, University of Washington;
4001 NE Stevens Way, Seattle, WA 98195
(206) 543-8131
TRAVEL INFORMATION:
http://www.ifscomm.org/index.php?main_page=page&id=4
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Hotel. Please click on www.watertownseattle.com for more
details.
END OF DAY 3
END OF CONFERENCE
4242 Roosevelt Way NE
Seattle, WA 98105
4
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