DDI-2007 program FINAL

Institute for Scientific Exchange, Inc. Presents:

DDI – 2007

10^th International Conference on Drug-Drug Interactions:

Scientific and Regulatory Updates and DDI Technologies in Depth: Enzyme Inhibition, Enzyme Induction and Drug-Transporter Interactions

June 24-26, 2007

Pre-Conference Workshop: In Vitro Evaluations of ADMET Drug Properties in Drug Development

June 24, 2007

Bellevue, WA, USA

Featuring experts from the following institutions: Amgen Inc.; APSciences; Boehringer-Ingelheim Pharmaceuticals, Inc.; BRI Biopharmaceutical Research Inc.; BRIVAL/IVAL, LLC.; CellzDirect, Inc.; Millennium Pharmaceuticals, Inc.; .; Novartis; NCI-NIH; Novartis Pharmaceuticals Corporation; Pfizer, Inc.; Pfizer Global R&D; Promega; SimCyp; Sonus Pharmaceuticals Inc.; Tufts University; University of Sheffield; University of Washington

REGISTER NOW

PARTICIPATING EXHIBITORS:

WE’VE MOVED

ISE, Inc.

8775 Centre Park Drive

#713

Columbia, MD 21045

(410) 869-9166

WE’VE MOVED

City of Bellevue, WA

The workshop is designed to provide novice and veteran practitioners with practical information on the application of in vitro ADMET experimental systems in drug development. The following will be emphasized

8:00 AM – 8:05 AM Exhibitor Presentation – BRI Biopharmaceutical Research, Inc.

Role of In Vitro Experimental Systems in Drug Development (Albert P. Li, APSciences Inc. and IVAL/BRIVAL, Columbia MD and Vancouver, BC)

Metabolic Stability and Drug-Drug Interactions (Chuang Lu, Millennium Pharmaceuticals Inc.; Cambridge, MA)

· high-throughput automated system using commercially available hardware and software for incubation and LC/MS/MS analysis

· Inducible P450 isoforms and P450 isoforms to be included in routine P450 induction studies

Toxicity Screening (Albert P. Li, APSciences Inc. and IVAL/BRIVAL, Columbia MD and Vancouver, BC, CANADA)

In Vitro ADME Screening Assays for Early Drug Discovery (Lilly Xu, Amgen Inc.; Thousand Oaks, CA)

LC/MS and LC/MS/MS Applications in ADME Studies (David Kwok, BRI Biopharmaceutical Research Inc.; Vancouver, BC)

Bioluminescent Approaches For In Vitro ADME/Tox (Jim Cali, Promega; Madison, WI)

· Bioluminescent assays that utilize firefly luciferase for sensitive, homogenous ADME/Tox applications

· Multiplexed cell-based assays for cytotoxicity and P450 induction at the transcriptional level and at the level of P450 enzyme activity

What is new in 2006-2007? (Sophie Chung and Isabelle Ragueneau-Majlessi, University of Washington; Seattle, WA) This presentation will provide an update on the literature on drug interactions in 2006-2007. This large body of papers will be classified according to the following categories: metabolism vs transport-based interactions; new substrates, inhibitors and inducers; most represented therapeutic classes and disease entities; largest AUC effects; advances in methodology; progress in vitro-in vivo correlations; noteworthy case reports; challenging and unexplained drug interactions.

Recently Approved Drugs: Drug Interaction Information in Labeling (Carol Collins, University of Washington, Seattle, WA) This presentation will highlight the drug interaction and QTc information as presented in product labeling for drugs approved in 2006 and 2007. Trends in the type of information presented including predicted drug interactions will be summarized. In addition, a comparison of product label and posted clinical review drug interaction information will be included.

FDA Guidance Document (Kenneth Thummel, University of Washington; Seattle, WA) FDA released a draft guidance document in September 2006 with explicit details on the performance of in vitro and in vivo drug-drug interaction studies. The practical and scientific aspects of this document will be reviewed.

In Vitro Drug-Drug Interaction Evaluation Using Intact Hepatocytes and 100% Human Plasma (Chuang Lu, Millennium Pharmaceuticals, Inc.; Cambridge, MA) Determining the in vivo inhibitor concentration at the enzymatic site (the “true” concentration) is critical for predicting the clinical DDIs, but it remains a technical challenge. Various approaches have been used in the literature to estimate the “true” human hepatic concentrations of inhibitors, and application of those to predict DDIs have shown some success. In the present study, a novel approach using cryopreserved human hepatocytes was applied in 100% human plasma to mimic the in vivo concentration of ketoconazole at the enzymatic site. The involvement of various CYPs in the metabolism of compounds of interest was quantitatively determined (reactive phenotyping). Likewise, the effect of ketoconazole on the activity of various CYPs was quantitated. Utilizing this information, the clinical DDI potential can be predicted without the need for estimation of ketoconazole concentration at the enzyme site.

Prediction of Cytochrome P450-Based Drug-Drug Interactions from In Vitro Inhibition and Inactivation Data (Robert L. Walsky, Pfizer Inc., Groton, CT) The use of in vitro reversible inhibition and time dependent inactivation kinetic parameters in scaling clinical drug-drug interactions (DDI) for human cytochrome P450 enzymes (CYP1A2, 2B6, 2C9, 2C19, 2D6, 3A) were examined using human P450 selective marker activities in pooled human liver microsomes. These data were combined with other parameters (systemic C_max, estimated hepatic inlet C_max, fraction unbound, in vivo P450 enzyme degradation rate constants estimated from clinical pharmacokinetic data, and f_m(CYP)) to predict increases in exposure to drugs, and the predictions were compared to in vivo DDI gathered from clinical studies reported in the scientific literature.

Mechanism-Based Enzyme Inhibition: A Critical Look at In Vitro Study Design and Implications for In Vitro-In Vivo Extrapolation (G.T. Tucker, University of Sheffield & Simcyp Ltd, Sheffield UK)

The inactivation of cytochromes P450 by metabolic products that form heme or protein adducts or a metabolic inhibitory complex (mechanism-based inhibition, MBI) leads to irreversible or quasi-irreversible loss of enzyme function, such that recovery from a decrease in drug clearance and the offset of drug-dug interaction requires synthesis of new enzyme. Quantitative prediction of these phenomena in vivo requires values of the inactivation parameters (k_inactand K_I) and estimates of enzyme turnover (k_deg). Issues related to the accurate determination of these values will be discussed and examples of in vitro-in vivo extrapolation will be presented.

Prediction of Time-dependent Inactivation of CYP3A in Hepatocytes: Evaluation of the Use of Microsomal Parameters to Predict Pharmacokinetic Drug Interactions. (Ping Zhao, Kent L Kunze¹, Caroline A Lee^2,Sonus Pharmaceuticals Inc, Bothell, WA; ¹University of Washington, Seattle, WA; ²Pfizer Global Research and Development, San Diego, CA) Human liver microsomes (HLM) and hepatocytes are extensively used to predict drug-drug interactions (DDI). The cellular integrity of hepatocytes makes them suitable for evaluating the predictability of HLM-generated kinetic parameters. We evaluated the time-dependent inactivation of CYP3A activity in cryopreserved human hepatocytes caused by well known inactivators. Large discrepancies were observed between the rates of inactivation in the two systems. Factors causing the discrepancies included nonspecific binding, metabolic consumption, active transport, and sequentially-formed inhibitory metabolites. Therefore, hepatocyte experiments can serve as an important checkpoint to prospectively evaluate the application of HLM data to predict in vivo DDI.

Prediction of Human Drug-Drug Interactions from Mechanism-Based CYP3A4 Inhibition in Human Hepatocytes (Lilly Xu, Amgen Inc.; Thousand Oaks, CA) Human liver microsomes (HLM) have served as an enzyme source for screening of new chemical entities (NCEs) as mechanism-based CYP inhibitors (MBI) in industry for decades. The data can be extrapolated to predict human drug-drug interaction potential. However, MBI-mediated clinical DDIs could be over-estimated from the data in HLM as compared to that in hepatocytes if the bio-activation by a CYP(s) is diminished by other enzymes (i.e. phase II enzymes) present in hepatocytes. In addition, hepatocytes as intact cells are more suitable to mimic the conditions (structural and physiological) in vivo than those in HLM. Therefore, we have investigated MBI of several known CYP3A4 inhibitors from primary human hepatocytes in comparison with that from HLM. Prediction of clinical DDIs using the two sets of in vitro MBI data will be presented. Pros and cons in utilization of human hepatocytes as an approach to evaluate MBI will be discussed.

Role of Inhibitory Metabolites in Drug-Drug Interactions (Nina Isoherranen, University of Washington; Seattle, WA) Ignoring circulating metabolites can lead to under-predictions of inhibitory drug-drug interactions. To accomplish accurate predictions, the inhibitory potency of parent drug and metabolites must be characterized in vitro and the plasma concentrations measured in vivo. The role of circulating metabolites to observed inhibitory drug-drug interactions is demonstrated in the inhibition of CYP3A4 after itraconazole, CYP2D6 after fluoxetine and CYP2C9 after sulfinpyrazone administration. For all three of these drugs, circulating metabolites are predicted to be responsible for the majority of the in vivo interaction.

In Vitro-In Vivo Disconnection: Studies of Nutrients and Natural Substances (David J. Greenblatt, Tufts University School of Medicine; Boston MA) During the last decade considerable research effort has been invested in the application of in vitro models to predict clinical drug interactions. Typically these models combine in vitro inhibition constants and anticipated inhibitor exposure to yield a quantitative forecast of changes in substrate drug clearance due to inhibitor coadministration in vitro. While predictive accuracy has been achieved in some cases, the modeling process continues to have significant limitations. An area of major predictive weakness occurs with inhibitors contained in herbal medicines, foods, and nutrients. This presentation will focus on mechanisms explaining the in vitro-in vivo disconnection for naturally-occurring metabolic inhibitors, with particular attention to fruit and citrus beverages.

Esterase Inhibition Attribute of Grapefruit Juice Leading to a New Drug Interaction (Suresh Balani, Millennium Pharmaceuticals, Cambridge, MA) This presentation will describe esterase inhibition as a new attribute of Grapefruit juice (GFJ) leading to drug interactions for ester prodrugs. GFJ inhibited esterase activity in vitro in animals and human, and in vivo in rats. Mechanistic studies leading to determination of relative contribution of CYP3A vs. esterase inhibition by GFJ and its ingredients will be discussed for a drug. These new esterase inhibition findings indicate that the potential of drug interaction between ester prodrugs and GFJ should also be considered in the clinic.

Assessing Enzyme Induction In Vitro: A Scientific and Regulatory Perspective (Edward L. LeCluyse, CellzDirect, Inc.; Pittsboro, NC) Enzyme induction represents a major discipline in the field of drug-drug interactions. The scientific concepts, the various approaches and endpoints to assess enzyme induction, and the regulatory requirements for enzyme induction studies will be reviewed.

Protocols for Enzyme Induction Studies (Nicky Hewitt, CellzDirect, Inc.; Pittsboro, NC) A review of a current survey of enzyme induction protocols in various industrial laboratories will be reviewed.

Human Hepatocyte Cryopreservation and Enzyme Induction (Albert P. Li, APSciences Inc. and IVAL/BRIVAL, Columbia MD and Vancouver, BC) Human hepatocytes represent an important experimental system for in vitro ADME studies. Recently, U. S. FDA has recommended cryopreserved human hepatocytes as an acceptable replacement for freshly isolated human hepatocytes. Induction studies require the use of plateable cells which, until recently, represent a major challenge in human hepatocyte cryopreservation. Recent advances in human hepatocytes cryopreservation will be reviewed, with emphasis on the success in our laboratory to cryopreserved human hepatocytes to retain high attachment efficiency for induction studies.

Evaluation of Drug-Transporter Interactions Using In Vitro and In Vivo Models (Cindy Xia, Millennium Pharmaceuticals, Inc.; Cambridge, MA) Drug transporters, including efflux transporters (the ATP binding cassette (ABC) proteins) and uptake transporters (the solute carrier proteins (SLC)), have an important impact on drug disposition, efficacy, drug-drug interactions and toxicity. Identification of the interactions of chemical scaffolds with transporters at the early stages of drug development can assist in the optimization and selection of new drug candidates. In this review, we discuss current in vitro and in vivo models used to investigate the interactions between drugs and transporters such as P-gp, MRP, BCRP, BSEP, OAT, OATP, OCT, NTCP, PEPT1/2 and NT. In vitro models including cell-based, cell-free, and yeast systems as well as in vivo models such as genetic knockout, gene deficient and chemical knockout animals are discussed and compared. The applications, throughput, advantages and limitations of each model are also addressed in this presentation.

Role of Transporters in Different Therapeutic Areas: From Systemic Disposition to Cellular Localization (Lisa von Moltke, Millennium Pharmaceuticals, Inc; Cambridge, MA) Drug transporter activity may be an important determinant of absorption, distribution and excretion characteristics for therapeutic substrates. The resulting systemic and tissue-specific exposure profiles may be considerations for use in particular disease states. In addition, transporter activity may play a significant role in intracellular substrate localization and homeostasis, with implications for understanding pathologic states and interventions.

Valsartan Interaction with Uptake and Efflux Transporters (Imad Hanna, Natalya Alexander, Novartis Pharmaceuticals Corporation, East Hanover, NJ) The trans-cellular movement of valsartan, a di-anionic angiotensin II receptor antagonist, is expected to be limited by its hydrophilic characteristics under physiological conditions. Despite this, valsartan exhibits good oral bioavailability indicating the possible involvement of transporters in its absorption and eventually in its excretion. Such transport mechanisms would include the concerted action of uptake and efflux transporters localized on the polarized membranes of enterocytes and hepatocytes. Studies aimed at the characterization of valsartan transport, and similar anionic compounds, under various conditions were performed. Incubation conditions included investigating the effects of pH, temperature, and transport protein inhibitors on the activity of drug transporters that may play a role in the disposition of valsartan.

Transporter Mediated Drug-Drug Interactions: Prediction of Clinical Outcome from In Vitro Data (Mitchell E. Taub, Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT) The clinical relevance of transporters is firmly established in terms of their potential to contribute to poor bioavailability, lack of efficacy due to limited exposure within target organs, or adverse reactions due to drug-drug interactions. As such, characterization of the potential interaction of drug candidates with transporters is an indispensable aspect of any successful research and development program. Methods for evaluating drug-transporter interactions, interpretation of data, and regulatory concerns will be discussed.

Role of Hepatic Transporters in the Disposition of Statins (Liyue Huang, Amgen Inc.; Cambridge, MA) Pharmacokinetic drug-drug interactions between HMG-CoA reductase inhibitors, statins and cyclosporin or gemfibrozil have been reported. Several statins including rosuvastatin and pravastatin are mainly excreted into bile as parent. This presentation will highlight hepatic uptake and efflux of statins with focus on BCRP-mediated transport of rosuvastatin. The contribution of hepatic transporters to the observed drug-drug interaction in the clinic will also be reviewed.

Intestinal Drug Metabolism and Transport (Mary Paine, University of North Carolina, Chapel Hill, NC) Many drugs, when taken orally, are subject to a number of elimination processes during their initial passage through a sequence of organs before reaching the general circulation. For some drugs, the extent of first-pass elimination can be large enough such that oral bioavailability is greatly reduced, which can then lead to a reduced clinical response. The small intestine, like the liver, is replete with drug metabolizing enzymes and transporters. Therefore, an understanding of these intestinal enzymes and transporters is essential, as they can represent an important determinant of the extent of first-pass drug elimination, as well as the probability and magnitude of drug-xenobiotic interactions.

Evaluation of Multidrug Resistance-linked P-glycoproteins from Mammalian Species Used in Preclinical Studies (Suresh V. Ambudkar, National Cancer Institute, NIH, Bethesda, MD) The product of ABCB1 (MDR1) gene, P-glycoprotein (Pgp) is expressed in a wide variety of tissues, and plays an important role in the pharmacokinetics and pharmaco-toxicology of xenobiotics. The interaction between Pgp and the test drug candidates is screened in early drug discovery stages. To extrapolate transport and pharmacokinetic data of the drug candidates obtained from in vitro and animal models to those in humans, it is important to investigate the differences or similarities among these mammalian Pgps. The drug-substrate specificity of human, African Green and Cynomologous monkey, dog, rat and mouse Pgp stably expressed in porcine LLCPK-1 cell line will be discussed.

About the Institute for Scientific Exchange

The mission of The Institute for Scientific Exchange, Inc. is to advance science via communication – (i. e. symposia, training courses, publications). The events held by the Institute are highly selective, timely, and of the highest professional caliber. One major goal of the Institute, as exemplified by this symposium, is to foster communication among industrial, regulatory, and academic practitioners. Please visit our web site at www.isciencex.com.

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.; 8775 Centre Park Drive, # 713; Columbia, MD 21045 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.

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PARTICIPATING EXHIBITORS:

HOTEL:

TRAVEL INFORMATION:

Reservations: Address: 11211 Main Street

Bellevue, WA 98004

Tel: 425-455-5240

Fax: 425-455-0654

TRAVEL INFORMATION: With easy access from Interstates 90 and 405, the Red Lion Hotel Bellevue is minutes away from Bellevue Square's 200 stores and boutiques, the business district and Meydenbauer Convention Center as well as local attractions and activities including golf, skiing, sailing, tennis and jogging trails. Downtown Seattle is just nine miles from the hotel, making it easy to visit favorites like the Space Needle, Pike Place Market and Pioneer Square or enjoy Sonics basketball, Seahawks football and Mariners baseball. We are also conveniently located just 3 miles from Bellevue Community College, 8 miles East of the University of Washington and Seattle University and 17 miles North of Seattle Tacoma International Airport.

General Information: We are a full-service hotel with 181 guest rooms decorated in a boutique-style with over-stuffed pillows, comforters and maple furnishings. Our new "Stay Comfortable" beds feature Sealy Pillowtop mattresses, linens and comforters on king or extra long, double-sized beds that suit the needs of both business and vacation travelers. In-room amenities include remote control televisions with over 50 stations including ESPN and CNN, pay-per-view movies, Nintendo®, two-line telephones with dataports, voicemail and free Net4Guests high-speed wireless Internet access available in all rooms and meeting space. Other amenities include a state-of-the-art business center, fully-equipped fitness center, seasonal outdoor pool, Hertz car rental office and complimentary parking. http://redlion.rdln.com/HotelLocator/HotelOverview.aspx?metaID=14

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., 8775 Centre Park Drive, Columbia, MD 21045 USA

Cancellation Policy

All cancellations are subjected to a $250.00 cancellation fee. Longer than 30 days, 100% refund (less cancellation fee). 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 January 21, 2005. Please submit cancellation and refund requests including transferring of registration to:

Fax: 410-869-9560; E-mail: nola@isciencex.com; Cancel Deadline: May 25, 2007

Registration Form ALSO AVAILABLE ONLINE AT WWW.ISCIENCEX.COM

Email to nola@isciencex.com or mail/fax completed form with remittance to: ISE, Inc. 8775 Centre Park Drive, # 713, Columbia, MD 21045, 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.

Academic/Government participants will receive a 50% discount.

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

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REGISTRATION FORM: DDI-2007

Event(s) (check all events registered)

Individual Course/Conference - $

DDI-2007

Preconference Workshop (full day)

06/24/2007

US $450.00 ______

(until May 15th, 2007)

US $550.00 ______

DDI-2007