Drug Transporters
Although the knowledge regarding the conduct of transporters assays and data interpretation has expanded dramatically over the past years, in vitro-to-in vivo and preclinical-to-clinical translation of transport data is still a very challenging field.
With the draft EMEA guidance, the ITC whitepaper and FDA regulation under way, performing well-designed transporter experiments has become crucial for pharmaceutical companies.
2. 12th – 14th April 2011 | Maritim pro Arte Berlin
Dear colleague, Sponsorship
Since IQPC's first meeting on clinically relevant drug transporters in 2009 considerable progress has been We have a variety of packages
made in understanding the influence of membrane transporters on drug absorption, disposition, metabo- available to suit your requirements.
lism and elimination. Although the knowledge regarding the conduct of transporters assays and data inter- For all Sponsorship and Exhibition
pretation has expanded dramatically over the past years, in vitro-to-in vivo and preclinical-to- opportunities call Neil Corteen:
clinical translation of transport data is still a very challenging field. +49 (0)30 20 91 32 75 or email
neil.corteen@iqpc.de.
With the draft EMEA guidance, the ITC whitepaper and FDA regulation under way, performing well-designed
transporter experiments has become crucial for pharmaceutical companies.
So don´t miss IQPC's second conference
For further information
CliniCally relevant drug transporters please visit our website
www.drug-transporters.com/SP or
Mechanistic modelling of transporter driven PK – Drug-drug interaction – contact Brijesh Patel on
Translation of transport data +49 (0)30 20 91 33 33 or email
brijesh.patel@iqpc.de.
12th – 14th April 2011 | Maritim pro Arte Berlin
which will bring together pharmaceutical and academic scientists. Areas of discussion will include:
Team Discounts
• Effective testing and modelling methodology We are offering attractive Team
• In vitro-to-in vivo and preclinical-to-clinical translation of transport data Discounts, please contact us!
• Impact of regulatory authorities and the ITC whitepaper
We are looking forward to meeting you in Berlin.
Kind regards
Sebastian Krzonkalla
Product Manager
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To Register | T +49 (0)30 20 91 33 33 | F +49 (0)30 20 91 32 10 | E brijesh.patel@iqpc.de | www.drug-transporters.com/SP
3. CoNFERENCE DAy oNE | Tuesday, 12th April 2011
09:00 Registration & coffee 13:15 Networking luncheon
09:30 Chairman´s welcome and opening address 14:15 Glial Cells: Secondary Barriers to Drug Permeability
H
ig
hl
Ph.D. Maarten T. Huisman, • Contribution of glial cells to the neurovascular unit
ig
ht
DMPK Belgium, Teamleader PK-lab Belgium & Leader barrier function
J&J Center of Expertise Transporters, • Localization and functional expression of ATP-Binding
Johnson & Johnson, Belgium Cassette (ABC) membrane transporters in glial cells
(astrocytes and microglia)
Absorption • Regulation of ABC transporters by HIV viral coat protein,
gp-120, in glial cells, a cellular target of HIV infection
09:45 The influence of drug transporters on drug absorption • Complexity of drug-transporter interactions in the
• Relevant transporters in the gut context of HIV-associated inflammation and oxidative stress
• uptake transporters Ph.D. Reina Bendayan,
• Efflux Transporters Professor and Associate Dean, Graduate Education,
Ph.D. Sven Stegemann, Department of Pharmaceutical Sciences, Leslie Dan
Director Global Pharmaceutical Business Development Faculty of Pharmacy,
Capsugel, Division of Pfizer, Belgium University of Toronto, Canada
Distribution / Metabolism / Elimination 15:00 Impact of regulatory authorities and the ITC Whitepaper
• Impact of FDA regulation
• Impact of ITC Whitepaper
10:30 Human uptake and efflux transporters and their role in
• Interpretation and application of the draft EMEA
hepatic drug absorption, metabolism, and elimination –
guidance
Focus on lIvER
• Japan
• Relevance of transport proteins for drug half-life, uptake,
Dr. Dietmar Weitz,
and action
Laboratory Head, MPK Metabolism & In vitro Systems,
• Drug uptake into human hepatocytes by OCT and OATP
Sanofi-Aventis Deutschland GmbH, Germany
proteins
• Drug efflux into bile / into the circulation by efflux
15:45 Refreshment break & networking
transporters (e.g. MRP2, MRP4, MDR1 P-glycoprotein)
• In vitro systems to measure uptake and efflux
transporters Transporters & Toxicity
• Pharmacogenetics of drug transporters
PD Dr. Anne Nies,
16:15 Renal organic anion transporters: Is regulation of
Head Membrane Transport Proteins,
expression involved in renal damage after ischemia?
Dr. Margarete Fischer-Bosch Institute of Clinical
• OAT1 (Slc22a6)
Pharmacology, Stuttgart
• OAT3 (Slc22a8)
University of Tübingen, Germany
• Regulation of expression
11:15 Refreshment break & networking • Renal ischemia and reperfusion
• Renal outcome
11:45 Focus on KIDNEy PD Dr. Christoph Sauvant,
H
ig
Role of organic ion transporters in the renal elimination Laboratory Head,
hl
ig
of drugs: clinical investigation using in vivo inhibitors
ht
University Halle-Wittenberg, Germany
• In vivo inhibitors for OAT1, OAT3, MATE1 and MATE2-K
• In vitro evaluation of transporter function using human 17:00 Closing remarks of the chairman
kidney slices and brush border membrane vesicles and end of conference day one
• Drug-drug interaction studies using probe substrates and
inhibitors in healthy subjects
• Endogenous substrates of renal organic ion transporters
Dr. Hiroyuki Kusuhara,
Associate Professor Department of Molecular PK,
University of Tokyo, Japan
12:30 Drug Transport across the Blood-Brain Barrier (BBB)
• Structure and function of the BBB
• Regulation and Modulation of transporters
• Models of the BBB
• Drug Delivery Systems for CNS-delivery
Prof. Dr. Gert Fricker,
Director at the Institute of Pharmacy and Molecular
Biotechnology,
University of Heidelberg, Germany
To Register | T +49 (0)30 20 91 33 33 | F +49 (0)30 20 91 32 10 | E brijesh.patel@iqpc.de | www.drug-transporters.com/SP
4. CoNFERENCE DAy TWo | Wednesday, 13th April 2011
08:30 Registration & coffee James Clarke,
Scientist, DMPK,
09:00 Chairman´s welcome and opening address GlaxoSmithKline R&D, UK
Ph.D. Sven Stegemann,
Director Global Pharmaceutical Business Development 13:00 Networking luncheon
Capsugel, Division of Pfizer, Belgium
14:00 Interplay of Metabolism and Transport in Determining
oral Drug Absorption and Gut Wall Metabolism:
Mechanistic Modelling of Transporter Driven PK & DDI
A Simulation Assessment Using the “Advanced
Dissolution, Absorption, Metabolism (ADAM)” Model
09:15 Introduction into in vitro / in vivo models Amin Rostami-Hodjegan, Professor of Systems
H
ig
• Overview of key in vitro / in vivo tools
hl
Pharmacology,
ig
• Advantages/Disadvantages
ht
School of Pharmacy and Pharmaceutical Sciences
• IVIVC
University of Manchester
Ph.D. Maarten T. Huisman,
Director of Scientific Development,
DMPK Belgium, Teamleader PK-lab Belgium & Leader
J&J Center of Expertise Transporters, Simcyp limited Blades Enterprise Centre
Johnson & Johnson, Belgium
14:45 Development of a novel human proximal tubule cell
Laurent Salphati, model to understand the renal handling of drug molecules
Scientist, • We have developed a fully differentiated Human primary
Genentech Inc., Member of the Roche Group, USA proximal tubule cell model
• Cell monolayers exhibit vectorial transport of key
10:45 Refreshment break & networking prototypic substrates
• We can quantify the contribution of individual
11:15 Transporter Pharmacoproteomics: Protein
H
transporters to the handling of drug molecules
ig
quantification for nonclinical and clinical research in
hl
ig
the industry and the hospital • We can identify key sites of drug-drug interactions
ht
• Introduction: Why transporter protein quantification is • We can study transporter expression and function in
important ? response to substrate exposure
• Methodology: How to quantify transporter protein by LC- Dr Colin D A Brown Ph.D, Epithelial Research Group
MS/MS ? (Detection limit, dynamic range, reproducibility) Institute for Cell & Molecular Bioscience,
• Application Medical School, Newcastle University
Quantitative evaluation of in vitro culture system
based on the transporter protein quantification 15:30 Refreshment break & networking
Quantitative evaluation of in vivo animal model based
on the transporter protein quantification in mouse,
16:00 Modelling of Transporter Driven DDI
monkey and human
Reconstruction of in vivo brain distribution for several • uptaketransporter and exportpumps relevant for DDI
drugs based on the mdr1a/MDR1 protein • hepatic and renal Transporters
quantification at the BBB • In vitro analysis of DDIs
Reconstruction of in vivo brain drug distribution in the • In vivo relevance of DDIs
diseased animal model based on the mdr1a/MDR1 PD Dr. Jörg König,
protein quantification at the BBB Institute of Experimental and Clinical Pharmacology
Quantitative evaluation of drug efflux transporters in and Clinical Toxicology,
the malignant glioblastoma and metastatic brain tumor Friedrich-Alexander-University Erlangen-Nürnberg,
patients based on the transporter protein quantification
Germany
• Perspective
Ph.D. Tetsuya Terasaki, Distinguished Professor,
Division of Membrane Transport and Drug Targeting 16:45 Transporter investigations to explain mechanisms of
Department of Biochemical Pharmacology and clinical DDIs
Therapeutics, Graduate School of Pharmaceutical • Astrazeneca drug development cases
Sciences, • Application of assays for uptake and efflux transporters
Tohoku University • Preclinical-to-clinical translation of transporter data
Johan Palm, PhD,
12:15 The mechanistic understanding and prediction of renal Clinical Pharmacology & DMPK, Mölndal,
drug-drug interactions with methotrexate: An industry AstraZeneca R&D Mölndal, Sweden
perspective
• An introduction to the PK and ADME of methotrexate
17:30 outlook Transporters
(with a focus on transporter mediated disposition)
• Methotrexate drug-drug interactions, a mechanistic Ph.D. Maarten T. Huisman,
understanding DMPK Belgium, Teamleader In Vitro Lab DMPK Belgium
• Prediction of methotrexate drug-drug interactions using and Leader J&J´s Center of Expertise Transporters,
in-vitro data from organic anion transporter assays Johnson & Johnson, Belgium
• Gaps in our knowledge around methotrexate drug-drug
interaction and how this is being addressed (includes 17:45 Closing remarks of the chairman
PBPK modelling efforts) and end of conference day two
To Register | T +49 (0)30 20 91 33 33 | F +49 (0)30 20 91 32 10 | E brijesh.patel@iqpc.de | www.drug-transporters.com/SP
5. INTERACTIvE WoRKSHoP DAy | Thursday, 14th April 2011
Workshop A
09:00 – 12:00
Neurovascular Unit and Biochemical Barrier Function
Limited drug penetration is an obstacle that is often encountered in the treatment of CNS diseases including human immuno-
deficiency virus type-1 (HIV-1) encephalitis (HIVE) and brain tumors. One mechanism that may contribute to this phenomenon is
the expression of ATP-binding cassette (ABC) drug efflux transporters [i.e., P-glycoprotein (P-gp), Multidrug Resistance-Associated
Proteins (MRPs/Mrps), Breast Cancer Resistance Protein (BCRP; also known as ABCG2)] at the blood-brain barrier (BBB). We
have demonstrated that ABC transporters are not only expressed in brain microvessel endothelial cells which form the BBB but
also in glial cells, the primary target of HIV infection in the brain. We propose that the localisation of these transporters in brain
parenchyma may also contribute to the low accumulation and altered distribution of several therapeutic compounds including
antiretroviral drugs and chemotherapeutic agents in the brain by creating a “secondary barrier” This workshop will discuss the
.
potential contribution of glial cells to the neurovascular unit barrier function and drug resistance in the context of HIV infection and
cancer.
Ph.D. Reina Bendayan, Professor and Associate Dean, Graduate Education Department of Pharmaceutical Sciences,
Leslie Dan Faculty of Pharmacy, University of Toronto, Canada
Workshop B
09:00 – 12:00
ABC of Modelling Transporter Data (I) - Principles and Practical Know How
The session will give a step-by-step guide to enable participants in understanding the terms applied within modelling are-
ana as applied to transporters. Transporter related experiments will be revisited and pitfalls will be highlighted to assist the
researchers in finding their way through the complex datasets obtained via various in vitro techniques. All participants will
have the opportunity of experiencing interactive problem solving sessions facilitated by experienced tutors.
Workshop Lead:
Amin Rostami-Hodjegan, Professor of Systems Pharmacology, School of Pharmacy and Pharmaceutical Sciences
University of Manchester, UK
Director of Scientific Development, Simcyp limited Blades Enterprise Centre, UK
Worksop Tutors:
Mr Matthew Harwood and Dr Fania Bajot, Research Scientists, Simcyp limited, Sheffield, UK
Workshop C ABC of Modelling Transporter Data (II) - Applications and Combining In vitro Knowledge
13:00 – 16:00 with Clinical observations
The session deals in details with complexity of the models related to transporters in gut and liver. The session touches
upon transporter modelling in brain and kidneyi before desending to practical examples involving the applications of the
modelling approach to answer observations related to oral bioavailability, hepatic clearance, drug-drug interactions (DDIs),
and drug distribution to different organs. Impact of population variability and approaches to handling genetic variations are
also discussed.
Workshop Lead:
Amin Rostami-Hodjegan, Professor of Systems Pharmacology, School of Pharmacy and Pharmaceutical Sciences
University of Manchester, UK
Director of Scientific Development, Simcyp limited Blades Enterprise Centre, UK
Worksop Tutors:
Mr Matthew Harwood and Dr Fania Bajot, Research Scientists, Simcyp limited, Sheffield, UK
Workshop D Species differences in drug transport and drug metabolism - do we have good enough
13:00 – 16:00 experimental models to work with?
What technologies should we be thinking of developing?
• Humanised animal models
• Computer PK-PD models
• Primary in-vitro human cell models ( hepatocyte sandwich, proximal tubule monolayers)
• Stem cell derived models?
Dr Colin D A Brown Ph.D, Epithelial Research Group, Institute for Cell & Molecular Bioscience, Medical School,
Newcastle University
To Register | T +49 (0)30 20 91 33 33 | F +49 (0)30 20 91 32 10 | E brijesh.patel@iqpc.de | www.drug-transporters.com/SP