Institute for Scientific Exchange, Inc. Presents:

DDI-2006 9th International Conference on Drug-Drug Interactions: Current Clinical and Regulatory Status; Transporter Based DDI and In Vitro-In Vivo Correlation   June 20-21, 2006 The Edgewater Hotel, Seattle, WA, USA

Featuring experts from the following institutions: The ADMET Group LLC; AstraZeneca; Chiba University; Merck & Co., Inc.; Millennium Pharmaceuticals, Inc.; Novartis Pharmaceutical Corp.; Qualyst, Inc.; Sankyo Co., Ltd.; The University of Sheffield and Simcyp Ltd; University of Washington

 

FEATURED EXHIBITORS:

 

      Seattle, Washington State, USA

  REGISTER

 

 

Sunday, June 18, 2006

Registration 3:00 PM - 5:00 PM

 

Monday, June 19, 2006: 

ISE Training Courses in Drug Development

 

Tuesday, June 20, 2006

8:00 AM – 9:00 AM Registration

 

8:45 AM - 8:55 AM – Exhibitor Presentation- SimCyp Limited

 

8:55 AM – 9:00 AM

Welcoming Remarks (Albert P. Li, The ADMET Group LLC, Rockville, Maryland)

9:00 AM – 9:30 AM  KEY NOTE PRESENTATION:  New Horizons in Drug Interactions: Science vs. Clinic (Rene H. Levy, University of Washington; Seattle, WA)

 

 

9:30 AM – 10:00 AM

Salient Features of the 2005-2006 Literature on Drug Interactions (Isabelle Ragueneau-Majlessi, University of Washington; Seattle, WA) This opening presentation will provide the participants with an update on some of the most significant advances in the literature on Drug Interactions during the last 12 to 18 months. It will highlight interesting publications and the current trends observed. The presentation will cover updates in metabolism-based drug interactions, including in vitro-in vivo correlations, regulatory issues, induction and transporters.

 

10:00 AM – 10:30 AM

Revised FDA Guidance for Drug-Drug Interaction Studies (Soraya Madani, Novartis Pharmaceutical Corp.; Rockville, MD) In the past decade, the issue of drug-drug interactions has been of great concern for both pharmaceutical industry and the health authorities.  Since the topic first captured the attention of the public in the mid 90’s with withdrawal of Seldane, FDA and other health authorities across the world have been trying to address the issue from regulatory perspective in multiple publications, including the regulatory guidances provided to the industry.  The first of such guidance to be published by FDA was made available to the public in April 1997. Since regulatory guidances are living documents, evolving with the scientific knowledge of the expert community, recently, in an effort to modify the 1999 guidance on drug-drug interaction, the FDA has published a preliminary Concept paper.  The concept paper which was discussed at the FDA Clinical Pharmacology advisory committee meeting in the fall 2004, is the basis for the revised Guidance on Drug-Drug interaction. The presentation will discuss both in vitro and in vivo drug interaction studies as they are presented in the Concept paper/revised guidance.  The presentation will also point out the area of additions and modifications comparing the concept paper/revised guidance with the previously published guidances on the topic of drug-drug interaction.

 

10:30 AM – 10:50 AM – BREAK

 

10:50 AM - 11:00 AM – Exhibitor Presentation- Advion BioServices, Inc.

 

11:00 AM – 11:30 AM 

FDA Clinical Pharmacology Update (Carol Collins, University of Washington; Seattle, WA) This presentation will review the highlights of the Final Rule: Requirements on Content and Format of Labeling for Human Prescriptions: Parts 1,2 and 3. In addition, it will summarize the associated final and draft guidances on labeling.  Other topics to be covered include: the FDA Clinical Pharmacology Subcommittee's recommendations for including pharmacogenomic data in the product labeling, key labeling revisions for approved drugs such as antidepressants and prescribing information for new molecular entities.

 

11:30 AM – 12:00 PM - PANEL DISCUSSION: Session 1

How effective are we in avoiding clinically significant DDI?  (Moderator:  Rene Levy).

 

 

12:00 PM – 12:30 PM

Importance of the Integration of Drug Transport and Metabolism for the Prediction of Drug – Drug Interactions (Kenneth R. Brouwer, and John Ansede, Qualyst, Inc., Research Triangle Park, NC) The utility of primary hepatocytes in the elucidation of the metabolism of a test compound is well recognized. These systems are also used to evaluate the potential for drug – drug interactions to occur in the metabolism of test compounds.  However, it is becoming increasingly recognized that the intracellular concentrations of test compounds are controlled by drug transporters.  In order to successfully predict the drug – drug interaction potential at the level of the parent compound or metabolite, it is critical to have an integrated system where the drug transporters and metabolic potential are optimized.  B-CLEAR^®, (Sandwich-cultured Hepatocytes) with intact canalicular networks and properly localized, functioning transport proteins has demonstrated the potential to evaluate transporter based hepatic drug – drug interactions for test compounds.  Additional studies will be discussed to extend this potential to the level of metabolites.

 

12:30 PM – 2:00 PM – LUNCH BREAK

 

2:00 PM – 2:10 PM – Exhibitor Presentation – XenoTech LLC

 

2:10 PM – 2:40 PM

Drug Interactions at the Blood Brain Barrier: Extrapolating from Rodents to Humans (Jashvant D. Unadkat, University of Washington, Seattle, WA) While considerable evidence is available from rodents that P-glycoprotein (P-gp) based drug interactions can be profound at the rodent blood-brain barrier (BBB), the importance of such interactions at the human BBB has not been determined.  Therefore, we have developed a state-of-the-art noninvasive and quantitative imaging technique to measure P-gp drug interactions at the human BBB using [¹¹C]-verapamil as a P-gp substrate and cyclosporine A as the P-gp inhibitor (1).  Then, using the same experimental conditions, we have determined if studies in rodents can predict P-gp drug interactions at the human blood-brain barrier.  Results and conclusions of these studies will presented. (1) Sasongko et al., Clin Pharmacol Ther. 2005 77:503-14.  Supported by NIH MH63641 and GM032165

 

2:40 PM – 3:10 PM

Prediction of Transporter-mediated Drug-Drug Interaction from the In Vitro Data (Yoshihisa Shitara⁽¹⁾, Toshiharu Horie⁽¹⁾ and Yuichi Sugiyama^(2);(1) Graduate School of Pharmaceutical Sciences, Chiba University ⁽²⁾ Graduate School of Pharmaceutical Sciences, The University of Tokyo; Tokyo, JAPAN)  Transporter-mediated hepatic uptake is an important determinant of hepatic elimination rate of drugs.  Thus, inhibition of the transporter-mediated uptake of drugs in the liver can cause a drug-drug interaction.  In our presentation, we introduce methods to quantitatively predict the hepatic clearance of drugs and the extent of transporter-mediated drug-drug interaction from the in vitro data using transporter expression systems. Transporters also play an important role in the renal elimination of drugs.  We also show the methods to predict the drug-drug interaction in the transporter-mediated processes of urinary excretion.

 

3:10 PM – 3:40 PM

Hepatobiliary Transporters in Drug-Drug Interactions and Toxicities: Case Studies from Millennium Pharmaceutics (Cindy Xia, Millennium Pharmaceuticals, Inc.; Cambridge, MA) Hepatobiliary transporters have great impact on drug disposition, drug-drug/endogenous substance interactions and drug-associated toxicity.  Exogenous or endogenous substance can be either taken up into hepatocytes by solute carrier transporters such as OATP, OCT, OAT and NTCP on the sinusoidal membrane or pumped into the bile duct by ABC transporters such as P-gp, BCRP, MRP and BSEP on the canalicular membrane.  In this presentation, the importance of hepatobiliary transporters in drug-drug interactions and toxicities in both in vitro and in vivo systems will be described.  The strategies to evaluate drug-transporter interactions in drug discovery and development at Millennium Pharmaceutics will also be discussed. 

 

3:40 PM – 4:00 PM – BREAK

 

4:00 PM - 4:10 PM – Exhibitor Presentation- Simulations Plus, Inc.

 

4:10 PM – 4:40 PM

Drug-Drug Interactions of HMG-CoA Reductase Inhibitors (Taro Tokui, Sankyo Co., LTD.; Tokyo, JAPAN) HMG-CoA reductase inhibitors (statins) are widely used for the treatment of hypercholesterolemia. Despite a low frequency of their side effects, myotoxic side effects including myopathy and rhabdomyolysis have a clinical importance. Recently, due to severe myotoxicity, cerivastatin was voluntarily withdrawn from the market. Pharmacokinetic drug-drug interactions of statins with concomitant drugs such as gemfibrozil are believed to be important causal factors for occurrence of the undesired effects. Contribution of the metabolic enzymes and transporters involved in clearance of the statins will be discussed.

 

4:40 AM – 5:30 AM - PANEL DISCUSSION: Session 2:  Transporter DDI in Drug (Moderator: Jashvant Unadkat)

 

END OF DAY ONE

 Wednesday, June 21, 2006

 

 

8:00 AM – 9:00 AM – Registration

 

8:50 AM – 9:00 PM – Exhibitor Presentation – Qualyst, Inc.

 

9:00 AM - 9:10 AM – Exhibitor Presentation- Absorption Systems

 

9:10 AM – 9:40 AM

In Vitro DDI Assays:  1995-2006 (Albert P. Li, The ADMET Group, Rockville, MD) The presentation will emphasize on approaches to enhance the efficiency of drug development.  For the past decade, in vitro assays for the evaluation of DDI have been used extensively in drug development.  The current practice of these in vitro assays will be reviewed, and relatively new approaches will be discussed.  A novel in vitro assay, Cytotoxic Drug-Drug Interactions (CDDI) assays, designed to evaluate toxic drug-drug interactions, will be presented. 

 

9:40 AM – 10:10 AM

Microsomal and Hepatocellular Scaling Factors for Use in the Prediction of Human In Vivo Metabolic Clearance (Zoe E. Barter, The University of Sheffield and Simcyp Ltd; Sheffield UK) Accurate extrapolation of in vitro data on drug metabolism to predict events in vivo (IVIVE) requires assimilation of large quantities of both drug specific and physiological information.  The initial focus of the Simcyp consortium, established in 1999, was in the gathering of such data for use in the prediction of metabolic drug-drug interactions.  Following success in this area, efforts have been expanded to the prediction of human in vivo metabolic clearance. In this context, particular emphasis has been given to the refinement of core IVIVE parameters such as microsomal and hepatocellular scaling factors and the incorporation of inter-individual variability.  The presentation will provide an overview of key factors involved in the determination of values of microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of human liver and their associated variability.  The importance of these scaling factors in providing accurate estimates of population means and inter-individual variability in metabolic clearance (with or without drug-drug interactions) will be emphasized.

 

10:10 AM – 10:40 AM

Quantitative Correlation of In Vitro and  In Vivo DDI Resulting from P450 Cooperativity (Wei Tang, Merck & Co., Rahway, NJ) Cytochrome P450s are major drug metabolizing enzymes that have been shown in vitro to exhibit cooperativity in liver microsomal and hepatocyte preparations.  We have developed animal models to demonstrate that P450 cooperativity takes place in vivo.  In this regard, using rabbit liver microsomes and a kinetic model incorporating two binding sites, the hepatic intrinsic clearance of R-warfarin via the 10-hydroxylation pathway (CL_int^W) was projected to be 6±1 and 128±51 ml/min/g liver, respectively, in the absence and presence of 21 mM unbound quinidine.  These estimates were consistent with the results from studies in which rabbit livers (n=5) were perfused in situ with R-warfarin or R-warfarin plus quinidine.  The CL_int^W increased from 7±3 to 156±106 ml/min/g liver after increasing the hepatic exposure of unbound quinidine from 0 to 21 mM.  These data suggest that changes in hepatic clearance resulting from stimulation of P450 activity can be projected based on estimates generated from corresponding liver microsomal preparations.

 

10:40 AM – 11:00 AM – BREAK

 

11:00 AM - 11:10 AM – Exhibitor Presentation - SOLVO Biotechnology

 

11:10 AM – 11:20 AM – Exhibitor Presentation – CellzDirect

 

11:20 AM –11:30 AM – Exhibitor Presentation – BRI Biopharmaceutical Research Inc.

 

11:30 AM – 12:00 PM

In Vitro-In Vivo Correlation of Mechanism-based P450 Inhibition (Raimund M. Peter, AstraZeneca, Alderley Park; Macclesfield, UK) Irreversible inhibition of drug-metabolizing CYPs can be observed for a number of marketed drugs in various therapeutic classes (e.g. oral contraceptives, macrolide antibiotics). Predicting the extent of these drug-drug-interactions in vivo based on in vitro experiments still presents a major challenge for drug discovery and development. This presentation aims to discuss the problems encountered in this approach, such as experimental study designs and pharmacokinetic parameters (e.g. dilution factor, protein half-life).  A critical evaluation of the different factors influencing in vitro-in vivo correlations should provide us with improved PK predictions for these drugs.

 

12:00 PM - 12:30 PM

In Vitro: In Vivo Correlation of P450 Inhibition and Induction (Kent Kunze, University of Washington, Seattle, Washington) In our laboratory, we have evaluated DDI using both in vitro systems as well as in vivo in laboratory animals.  In vivo experimental design for the evaluation of DDI will be presented.  Comparison of in vitro and in vivo results will be presented.  The clinical significance of weak in vitro P450 inhibitors and inducers will be discussed.

 

12:30 PM - 1:00 PM

Induction-mediated Drug Interactions: In Vitro Assessment and Clinical Relevance (Edward L. LeCluyse, CellzDirect, Inc.; Pittsboro, NC) The induction of drug clearance pathways, including phase I/II enzymes and transporters, can have important clinical consequences. Drugs that are inducers of drug-metabolizing enzymes and transporters can increase the clearance of other drugs that are substrates for the induced enzyme(s) resulting in a decreased therapeutic effect.  Alternatively, induced bioactivation of drugs, such as acetaminophen, can lead to increased risk of hepatotoxicity.  During the past several years, significant advances have been made in our knowledge of the mechanisms that regulate the expression of genes that determine drug clearance.  Nuclear receptors, such as the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR), have been recognized as key mediators of drug-induced changes in the expression of CYP enzymes, as well as of phase II enzymes and transporters. However, species differences in nuclear receptor activation are significant and it is clear that prediction of CYP induction in humans from data derived from most animal models can be problematic. As such, in vitro human-relevant model systems have become increasingly used to evaluate enzyme induction. During this presentation, our current understanding of the mechanisms of enzyme induction and the in vitro methods for assessing the induction potential of new drugs will be reviewed.  These approaches will be discussed in light of the revised FDA guidance on assessing drug-drug interactions, which outlines the proper conduct of in vitro induction studies. 

 

1:00 PM - 1:30 PM  -  PANEL DISCUSSION: Session 3

(Moderator:  Bernard Murray)

 

1:30 PM – 1:40 PM Concluding Remarks (Albert P. Li)

 

END OF CONFERENCE 

   REGISTER

 

POSTER PRESENTATIONS:

 

Poster Presentations are always encouraged.  Please submit your poster abstract for approval by the organizing board by May 30^th.  Poster size should be no larger than 3 feet high by 7 feet long.  Abstracts of posters will be included in the participant binder and in the ISE website.  There is no formal poster presentation scheduled.  All posters will remain displayed throughout the conference.  Please be prepared to display your poster during registration on Monday, June 19^th or before the first session begins on Tuesday, June 20^th.  Poster presenters will have ample time for discussion during breaks and the Panel discussions. Submit posters abstracts for approval to Nola Mahaney, VP, Operations; ISE, Inc.; 5707 Calverton Street, Suite 2C; Baltimore, MD 21228 or fax at (410) 869-9560 or email file attachment to nola@isciencex.com.  Approved poster presenters are responsible for completing a conference attendance registration form and payment of fee (visit www.isciencex.com/register.htm) and for the shipping of the poster itself.  Please contact Nola Mahaney for any questions or concerns.  Please refer to “Travel Information” for hotel address and shipping information.

 

PARTICIPATING EXHIBITORS:

 

  

Hotel Information

 

Travel Information:

Seattle’s only waterfront hotel. All the makings of a breathtaking vacation await you at The Edgewater. Nestled on Seattle’s waterfront at Pier 67, we’re surrounded by beauty: The majestic Olympic Mountains. The sparkling waters of Elliott Bay. And the velvety-pink sunsets of the Northwest sky. We’re in the heart of downtown, so you’ll be within walking distance to the city’s favorite sites. But you just might decide to relax right here, soaking up the view beside a river-rock fireplace.

 

Hotel Information:

The Edgewater Hotel, 2411 Alaskan Way, Pier 67
Seattle, Washington (WA) 98121 Hotel Direct (Tel) 206.728.7000 (Fax) 206.419.4119 Reservations 800.624.0670

http://www.edgewaterhotel.com/default.aspx?pageid=reservation

Please ask for “DDI-2006” block for ISE, Inc.

 

Early Registration Discount: (SAVE $$$ until April 3, 2006)

 

Exhibitors:            US$2000.00 (DDI-2006) ______

                                US$2000.00 (ETS-2006)______

                                US$3000.00 (both events)______

 

 

Contact Nola Mahaney for Exhibitor or Sponsorship Opportunities at nola@isciencex.com, or phone (410) 869-9166); or visit www.isciencex.com/exhibitors

 

Academic/Government participants will receive a 50% discount. 

 

PLEASE NOTE WHICH PROGRAM YOU WISH TO ATTEND IF REGISTERING FOR MULTIPLE PROGRAMS.

 REGISTER

 

Event(s) (check all events registered)	Individual Course/Conference - $ (Check if only registering for one single event)	Special Combination Discounts:  Check one of the combinations if registering for more than one event Early Registration Discounts Available (see below)
Tutorial 1 06/19/2006	US $400.00 ______	Both Tutorials: US$800.00 __________   1 Tutorial and 1 Conference: US $1700.00 _______
Tutorial 2 06/19/2006	US $400.00 ______	2 Tutorials and 1 Conference: US$2000.00 __________   Both Conferences: US $2500.00 __________
DDI-2006 06/20-06/21/2006	US $1500.00 _______	1 Course and 2 Conferences:  US$2700.00 ___________   All Four Events:  US $2900.00 ___________
ETS-2006 06/22-06/23/2006	US $1500.00 _______

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 REGISTER

  

Payment

Payment may be made by check or credit card.  Checks should be made in US $, payable to Institute for Scientific Exchange, Inc.  Mail to: ISE, Inc., 5707 Calverton Street, Suite 2C, Baltimore, MD 21228, USA

 

Cancellation Policy

All cancellations are subjected to a $250.00 cancellation fee. Longer than 30 days, 100% refund (less $250.00). Less than 30 days, no refund but registration may be transferred to another person.  All refund requests must be in writing.  All refunds will be issued after the meeting has occurred. No refunds requests will be accepted after May 19, 2006. Please submit cancellation and refund requests including transferring of registration to:

 

Fax:  410-869-9560

E-mail: nola@isciencex.com

Cancellation Deadline: May 19, 2006

 

Email to nola@isciencex.com or mail/fax completed form with remittance to: ISE, Inc. 5707 Calverton Street, Suite 2C, Baltimore, MD 21228, USA; FAX No:  (410) 869-9560.  Payment may be made by check in US$, payable to Institute for Scientific Exchange, Inc. or by credit card.