DDI-2008 11th International Conference on Drug-Drug Interactions (DDI-2008)

Venue: Red Lion Hotel Fifth Avenue

Location: Seattle, Washington, United States

Event Date/Time: Jun 02, 2008 End Date/Time: Jun 04, 2008
Registration Date: Jun 04, 2008
Early Registration Date: May 02, 2008
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Description

June 2, 2008

7:00 AM – 8:00 AM – REGISTRATION

8:00 AM – 9:00 AM
Scientific Concepts of Time-dependent P450 Inactivation (Magang Shou, Amgen Inc.; Thousand Oaks, CA) Drug-drug interactions (DDIs) represent a serious concern in the discovery and development of new drugs. Mechanism-based CYP inhibition (MBI) is a common cause of the DDIs via a significant change in the exposure of one drug (victim) caused by a second drug (perpetractor). In this presentation the concepts and experimental approaches of MBI, screening of new chemical entities (NCEs) and prediction of the human DDIs from in vitro MBI data at pharmaceutical settings will be reviewed.

9:00 AM – 10:00 AM
Recombinant CYP and liver microsomal time-dependent inhibition assays (Chuang Lu, Millennium Pharmaceuticals, Inc.; Cambridge, MA) Basic concepts and experimental procedures will be discussed for the evaluation of time-dependent inhibition potential of drug candidates. It is important to choose different methods for different compounds, such as for strong or weak TDI, TDI which also show reversible inhibition, etc. Mechanistic studies using recombinant CYPs will also be presented.

10:00 AM – 10:30 AM – BREAK

10:30 AM – 11:30 AM
Time Dependent Inhibition Studies Using Human Hepatocytes (Dermot McGinnity, AstraZeneca; Loughborough, Leics, England) Primary human hepatocytes in culture are commonly used to evaluate CYP induction via an enzyme activity endpoint. However, time-dependent P450 inhibition (TDI) can confound data interpretation in this system. In our laboratory, TDI has been characterised using cultured human hepatocytes and the data compared to results generated in recombinant P450s and human liver microsomes. Together with a P450‑selective substrate cassette approach, cultured human hepatocytes provide a sensitive system for studying TDI. In this lecture, the use of hepatocytes for studying TDI as well as the implications for P450 induction studies will be discussed.

11:30 AM – 12:30 PM
Cytotoxicity of Time-dependent Inhibitors in Human Hepatocytes (Albert P. Li, APSciences, Inc. and IVAL, LLC.; Columbia, MD) Human hepatocytes represent an experimental system with which P450 inhibition can be studied. The presence of an intact plasma membrane and complete, uninterrupted enzyme pathways and cofactors allow the generation of data more relevant to humans in vivo than data using cell fractions such as liver microsomes. As the hepatocytes are living cells, it is necessary to study P450 inhibition under conditions which would not lead to cytotoxicity, as a decrease in cell viability will lead to a decrease in P450 activities. The routine assay procedures for cell viability determination and the cytotoxicity of known time-dependent P450 inhibitors under various experimental conditions (e.g. incubation time; solvents) will be presented.

12:30 PM – 1:00 PM – PANEL DISCUSSION and CLOSING REMARKS

END OF PRE-CONFERENCE

1:00 PM – 2:30 PM – LUNCH BREAK

Main Conference

DDI-2008

11th International Conference on Drug-Drug Interactions

Session I: General Overview of DDI Status

Chair: Rene Levy

2:30 PM – 3:00 PM – REGISTRATION

3:00 PM – 3:15PM – OPENING REMARKS
René Levy, University of Washington, Seattle, WA

3:15 PM – 3:25 PM - EXHIBITOR PRESENTATION

3:30 PM – 4:15 PM
NMEs Approved in 2007-2008 (Carol Collins, University of Washington; Seattle, WA) This presentation will discuss information found in the NDA and product labeling pertinent to drug interactions for drugs approved in 2007-2008. Emphasis will be placed on FDA comments extracted from the NDAs that address issues not covered in the draft guidance, Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling (http://www.fda.gov/cder/guidance/6695dft.pdf). We will also evaluate prescribing information regarding drug interactions in the context of the therapeutic use of the product.

4:15 PM – 5:00 PM
Literature review 2007-2008: Clinical Studies (Houda Hachad, University of Washington; Seattle, WA) This presentation will provide an update on the literature on drug interactions in 2007-2008. This large body of articles will be classified according to the following categories: metabolism versus transport-based interactions; new substrates, inhibitors and inducers; most represented therapeutic classes and disease entities; largest AUC effects; advances in methodology; noteworthy case reports; challenging and unexplained drug interactions.

END OF DAY 1

DDI-2008 - June 3, 2008

Session II: Enzyme Inhibition and Induction

Chair:

7:00 AM – 8:00 AM – REGISTRATION

7:50 AM – 8:00 AM - EXHIBITOR PRESENTATION

8:00 AM – 8:45 AM
Significance of Time-Dependent P450 Inhibition in Drug-drug Interactions and Drug Toxicity (Larry Wienkers, Amgen Inc.; Seattle, WA) The inhibition of cytochrome P450 can be reversible or irreversible. Mechanism-based inhibition (MBI) is an irreversible inhibition where a covalent bond is formed between a reactive metabolite and the active site of the enzyme, resulting in drug–drug interactions or if the reactive intermediate is released toxicity. In this instance, metabolic activation of a relatively inert functional group to reactive electrophilic intermediates is required for MBI. As a consequence, a thorough examination of the biochemical reactivity of functional groups in a drug candidate is essential from a development perspective. In the current presentation, experimental strategies in the detection and characterization of reactive intermediates in P450 MBIs will be discussed.

8:45 AM – 9:30 AM
Time-dependent and Non-time Dependent P450 Inhibition Assays with Intact Human Hepatocytes (Dermot McGinnity, AstraZeneca; Loughborough, Leics, England) Human hepatocytes have been used for the study of both reversible and time-dependent inhibition of CYPs but it is notable that investigations of inhibitory mechanisms remain under represented compared to studies on metabolism and induction. This is likely due to the relative accessibility of rCYPs and their overall applicability in predicting clinically relevant DDI. As primary hepatocytes provide the closest in vitro model to human liver they may offer advantages when predicting clinical DDI. There is, however, little published comparative data of inhibition constants generated in rCYPs and human hepatocytes and the use of such data for predicting DDI. Data generated in this laboratory demonstrates IC50, unbound values generated in human hepatocytes, using probe substrates specific to the CYP isoform, were similar to those determined using the respective recombinant CYP with some notable exceptions. Primary human hepatocytes in culture are commonly used to evaluate CYP induction via an enzyme activity endpoint. However, time-dependent P450 inhibition (TDI) can confound data interpretation in this system. In our laboratory, TDI has been characterised using cultured human hepatocytes and the data compared to results generated in recombinant P450s and human liver microsomes.

9:30 AM – 10:15 AM
Difficulties Associated with the Interpretation of CYP34A Time-Dependent Inhibition Data (Michael Schrag, Array Biopharma; Boulder, CO) It is standard industry practice that compounds in discovery and development are screened for the potential to cause drug-drug interactions via time dependent inhibition (TDI). Since CYP3A4 plays a prominent role in drug oxidation, TDI of this enzyme is often assessed early in the discovery process. One assay that is frequently used to screen for TDI is the dilution assay. This talk will focus on the difficulties of interpreting CYP3A4 TDI data in early screens.

10:15 AM – 10:45 AM – BREAK

10:45 AM – 10:55 AM - EXHIBITOR PRESENTATION

10:55 AM – 11:40 AM
Prediction of CYP3A4 Induction Mediated Drug-Drug Interactions from In Vitro Data (Magang Shou, Amgen Inc.; Thousand Oaks, CA) CYP induction is not generally a concern for safety and however can yield serous therapeutic failures, particularly those with a narrow therapeutic index. To date, little has been known for prediction of CYP3A4 induction mediated DDIs from in vitro approaches (e.g. primary hepatocytes). In this presentation, the predictive models, prediction and in vitro in vivo correlation of in vivo CYP3A4 induction from in vitro data will be described and the factors that possibly limit the prediction will be discussed.

11:40 AM – 12:25 PM
Consideration of Intrahepatic Free and Bound Drug Concentrations in IVIVC (Chuang Lu, Millennium Pharmaceuticals, Inc.; Cambridge, MA) The use of either free or total drug concentrations in in vitro – in vivo correlation (IVIVC) dependents solely on the compound and study conditions. The concept of free intrahepatic concentration will be discussed. Examples of application of either free or total concentration to predict clinical drug-drug interactions will be presented.

12:25 PM – 2:00 PM – LUNCH BREAK

2:00 PM – 2:10 PM - EXHIBITOR PRESENTATION

2:10 PM – 2:55 PM
Simultaneous Assessment of Induction and Time-dependent Inhibition in Cultures of Primary Human Hepatocytes (Stephen S. Ferguson, Christopher B. Black, Edward L. LeCluyse1 CellzDirect, Inc., Durham, NC) Primary human hepatocytes are recognized as the “gold standard” model system for the assessment of cytochrome P450 induction potential in humans. This is due primarily to their characteristic under appropriate culture conditions of retaining the appropriate molecular signaling pathways involved in the control of CYP450 expression levels in human liver. These cultures represent a dynamic, responsive cellular system that has been shown to effectively model drug metabolism, induction, and inhibition in vitro. We have utilized this model system to simultaneously assess mRNA expression, protein content, and enzymatic activity with several classes of xenobiotics known to cause pharmacodynamic interactions in humans (e.g. inducers, inhibitors, time-dependent inhibitors, dual inhibitor/inducers). By using time as a tool to distinguish the relative contributions of inhibition and induction to CYP450 expression and enzymatic activity, we have characterized these various classes of effectors, and this has revealed interesting dynamics in their effects on CYP450 expression and metabolic activity. We further demonstrate that compounds known to induce and inhibit CYP450s may have differential effects on individual isozymes, therefore, classification of induction pathways and modes of inhibition is important for effective prediction of induction and/or inhibition potential. These findings have implications on our understanding of the dynamic and simultaneous processes of inhibition and induction in the liver, and outline a useful in vitro approach to more effectively characterize compounds that are found to be dual inducers and inhibitors of CYP450 activity.

2:55 PM – 3:30 PM – PANEL DISCUSSION

3:30 PM – 4:00 PM – BREAK

4:00 PM – 4:10 PM - EXHIBITOR PRESENTATION

Session III: Transporters

Chair:

4:10 PM – 4:55 PM
Kinetic Evaluation of Compounds as Substrates or Inhibitors for Transporters with Cell-based Assays and its Application (Steven Louie, PKDM, Amgen; Thousand Oaks, CA)

4:55 PM – 5:40 PM
Mechanistic Evaluation of Phase II Metabolite Excretion Pathways: Kinetic Consequences of Active Transport Inhibition on Exposure. (Maciej J. Zamek-Gliszczynski, Lilly Research Labs; Indianapolis, IN) Hydrophilic glucuronide and sulfate metabolites are excreted from both the site(s) of formation and the body via active transport. Bcrp and Mrp-2, -3, and -4 have been identified as transporters involved in this process using both gene-deficient animal models and in vitro systems. Ablation of a given transport pathway was shown to increase exposure to polar metabolites by a factor of 1/(1-fe), where fe is the fraction excreted via the intact pathway. This relationship is an important consideration for drug-drug interactions involving pharmacologically-active and toxic metabolites, as well as parent drugs cleared predominantly by active excretion.

END OF DAY 2

6:30 PM – 9:00 PM – RECEPTION SPONSORED BY:
University of Washington Metabolism and Transport Drug Interaction Database Team

Main Conference - June 4, 2008
7:00 AM – 8:00 AM – REGISTRATION

7:50 AM – 8:00 AM - EXHIBITOR PRESENTATION

Session III: Transporters CON’T

Chair:

8:00 AM – 8:45 AM
Genetic Variation in Transport Proteins and Drug Response (Reinhold Kerb, AstraZeneca; Stuttgart, Germany and Dr. Margarete Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart and Clinical Pharmacology, University of Tübingen, Germany)The emerging role of hereditary polymorphisms in efflux and uptake transport proteins for drug efficacy, - safety and tolerability is highlighted suggesting these need to be considered in drug discovery and development to better understand variability in drug disposition and response and drug-drug interactions.

8:45 AM – 9:30 AM
Non-Pgp Transporter Assays: Relevance to prediction of Drug Interactions. (Alexander Treiber, Actelion; Allschwil, Switzerland)

9:30 AM – 10:15 AM
Answering the Transporter Question Earlier (Greg Loewen, XenoTech; Lenexa, KS) Uptake and efflux transporters play a pivotal role in the absorption, distribution, metabolism and excretion (ADME) of drugs. Compounds that interact with transporters can cause drug-drug interactions by altering the clearance, efficacy and toxicity of co-administered drugs. New technologies are expanding the range and increasing the speed at which these drug-transporter interactions can be investigated. This presentation will review established technologies and new developments in assessing drug-transporter interactions.

10:15 AM – 10:45 AM – BREAK

10:45 AM – 10:55 AM - EXHIBITOR PRESENTATION

Session IV: DDI of Biologicals

Chair:
10:55 AM – 11:40 AM
Pharmacogenetics of Pgp in Patients with Leukemia: Implications for DDI and Therapy (Rodney Ho, University of Washington; Seattle, WA)

11:40 AM – 12:25 PM
Pharmacokinetic Drug-Drug Interactions for Therapeutic Monoclonal Antibodies - Clinical Relevance and Future Perspectives (Honghui Zhou, Johnson & Johnson Biotechnology, Immunology & Oncology; Malvern, PA) Recently a certain amount of clinically relevant information has begun to emerge on drug-drug interaction potential of therapeutic monoclonal antibodies. In contrast to a small-molecule drug, investigating the drug-drug interaction potential of a therapeutic monoclonal antibody is inherently complicated and challenging. Some important drug-drug interactions for therapeutic monoclonal antibodies will be highlighted, and practical considerations as well as future perspectives on this topic will also be discussed.

12:25 PM – 1:00 PM – PANEL DISCUSSION AND CLOSING REMARKS

END OF CONFERENCE

Venue

1415 Fifth Ave
Seattle
Washington
United States
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