PRE-CONGRESS SYMPOSIUM – PERSONALIZED IMMUNOSUPPRESSIVE THERAPY  

Saturday, October 3, 2009, 0815-1745 

0830-0910 Translational molecular markers will define the future of transplantation: from cage to clinic 0910-1025 Biomarkers 1055-1210 Clinical impact of pharmacogenetics 1340-1545 1340-1545 Clinical transplantation and large trials 1615-1730 What's new from Pharmaceutical industries     0815-0830  Introduction P. Wallemacq, Brussels, Belgium   0830-0910 Plenary Lecture 0830-0910  Translational molecular markers will define the future of transplantation: from cage to clinic Uwe Christians, MD, PhD, Professor and Vice Chair Research, Clinical Research & Development, Department of Anesthesiology, University of Colorado Denver, Denver, USA Click here for Description of this presentation The chronic loss of kidney function due to rejection in kidney transplant patients and/ or immunosuppressant toxicity in transplant patients in general has a negative impact on overall clinical outcome. Clinical diagnostic tools currently used for monitoring kidney function in transplant patients are either not very sensitive and specific such as creatinine in serum or are associated with significant risks such as the procurement of kidney biopsies. Modern technologies such as genomics, proteomics and metabolomics allow for screening for and development of new molecular marker with potentially improved sensitivity and specificity and recently the EMEA/FDA has approved the use of protein markers such as KIM-1, clusterin and trefoil factor 3 for monitoring kidney function during pivotal pre-clinical toxicology studies. This presentation will critically review status and current developments in the field of kidney dysfunction markers and their future potential in the long-term management of transplant patients. ------------------------------------------- Click here for Objectives of this presentation At the conclusion of this session the participant will understand: • The discovery, qualification and development of molecular markers into diagnostic tools; • The current position of FDA and EMEA on protein kidney dysfunction markers in drug development; • The advantages and disadvantages of protein kidney dysfunction markers; • The potential of metabolite patterns as markers for monitoring of kidney function; • How these markers can improve the management of transplant patients; • Can these markers be used to differentiate between chronic rejection and immunosuppressant toxicity in kidney transplant patients?. ------------------------------------------- Click here: Uwe Christians biography Uwe Christians, MD, PhD Uwe Christians received his M.D. and Ph.D. in Experimental and Clinical Pharmacology and Toxicology from the Medizinische Hochschule Hannover, Germany. He is a board certified pharmacologist, toxicologist and clinical pharmacologist with post-doctoral training at the University of California, San Francisco, and Stanford University. Dr. Christians is currently a Professor in the Department of Anesthesiology at the University of Colorado Denver and an adjunct Professor of Pharmacology and Toxicology at the Medizinische Hochschule Hannover, Germany. He is also the director of the Clinical Nutrition Research Unit Mass Spectrometry Core. Dr. Christians has published more than 150 research articles and book chapters. Research projects and interests include: Therapeutic drug monitoring and clinical pharmacokinetics, drug metabolism, drug transport and drug interactions, mechanisms of drug toxicity, drug eluting stents, new preclinical and clinical drug development strategies, and the development of toxicodynamic diagnostic monitoring strategies based on biochemical and protein profiling technologies. -------------------------------------------       0910-1025 Biomarkers Chairs: Pierre Wallemacq, Brussels, Belgium, and Teun van Gelder, Rotterdam, Netherlands 0910-0935  New approaches on immunosuppression monitoring: the role of cytokines and cell activation surface markers Mercè Brunet, Head of Pharmacology and Toxicology Department, Biomedical Diagnostic Center, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona University, Spain Click here for Description of this presentation Previous studies indicate that there is a medical need for surrogate biomarkers, which enables prediction of long term outcomes after transplantation and a subsequent personalized immunosuppressive therapy. Several cytokines and specific T-cells surface antigens have been evaluated as surrogate biomarkers that may reflect the specific mechanism of an immunosuppressive drug, the personal response to a particular drug, and some of them may also be predictive of the risk of rejection or drug-toxicity. The analytical aspects and standardization for the measurement of these surrogate biomarkers are of critical importance to evaluate the clinical impact of this pharmacodynamic monitoring in achieving a personalized treatment in transplant recipients. ------------------------------------------- Click here for Objectives of this presentation At the conclusion of this session the participant will understand: • Specific analysis for some cytokines strongly related with the mechanisms of action of some immunosuppressive drugs; • Role of these cytokines in assessing the risk of rejection and/or as a predictive biomarkers for personal response to a particular drug; • Correlation between pharmacokinetics and pharmacodynamics (drug exposure and cytokine expression). ------------------------------------------- Click here: Mercè Brunet biography Mercè Brunet PhD Graduated as a Philosophy Doctor from the Faculty of Pharmacy of Barcelona, Spain. Currently is the Head of Pharmacology and Toxicology Department of the Biomedical Diagnostic Center at the Hospital Clínic of Barcelona. IDIBAPS. Barcelona University. Coordinator of the Biomarker Working Group of the Cientific Committee of Immunosuppressive drugs of the IATDMCT. New Councillor of the IATDMCT (2009-2011) Field of research: Analysis of some biomarkers that may reflect the personal response to immunosuppressive drugs. Main purpose: Therapeutic drug monitoring, based on the combination of pharmacokinetic and pharmacodynamic parameters, as a base to achieve a personalized tretament. -------------------------------------------   0935-1000  The role of CD4 ATP measurement to achieve personalized immunosuppression in adult and pediatric transplant population Michael Oellerich, FFPath (RCPI),FRCPath, Director Dept. of Clinical Chemistry, George-August-University, University Medical Center Göttingen, Department of Clinical Chemistry / Central Laboratory, Göttingen, Germany Click here: Michael Oellerich biography Prof. Dr. med. Dr. h.c. Michael Oellerich, FFPath (RCPI),FRCPath Professor Dr. med. Dr. h.c. Michael Oellerich is a chemical pathologist (Facharzt für Laboratoriumsmedizin) and chairman of the Department of Clinical Chemistry / Central Laboratory at the Medical Faculty (UMG) of the Georg-August-University Göttingen, Germany. He received the honorary Fellowship of the Faculty of Pathology of the Royal College of Physicians of Ireland (FFPath RCPI) and the Fellowship of the Royal College of Pathologists (FRCPath) in 2006 as well as the honorary membership of the Romanian Society of Laboratory Medicine in 2007. From 1996 – 1998 he served as dean of the Faculty of Medicine and as the deputy of the chief executive for research and teaching on the executive board for the Medical Center and Faculty of Medicine from 1999 - 2004. He was president of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) from 1997 to 1999, president of the German Association for Laboratory Medicine from 2001 – 2002, president of the German United Association for Clinical Chemistry and Laboratory Medicine (2003-2005) and secretary-treasurer of the World Association of Societies of Pathology and Laboratory Medicine (WASPaLM) from 2005-2007. Currently he is president of WASPaLM. Since 1999 he is a member of the Steering Committee of EUROLIFE, a network of European centers of excellence in life sciences. He is Editor-in-Chief of the journal Therapeutic Drug Monitoring and Associate Editor of Clinical Chemistry. He was Associate Editor of Clinical Biochemistry (1996 – 2007). His current research interests are in the fields of therapeutic drug monitoring, the metabolism and pharmacokinetics of immunosuppressive drugs as well as pharmacogenetics. Further topics include liver injury, analytical techniques (e.g. LC-MS/MS) and molecular diagnostics. He and his collaborators have authored more than 350 articles contributed to scientific journals and book chapters. He received the Ludolf-Krehl Award of the S.W. German Soc. for Internal Medicine in 1971, the IATDMCT Charles Pippenger Award for Outstanding Contributions to Therapeutic Drug Monitoring in 2001, the 2002 Canadian Society of Clinical Chemists Travelling Lectureship Award, the Professor-Landbeck-Award 2004, Society for Thrombosis and Hemostasis Research, Hamburg 2004 and the Perth PathCentre Visiting Lectureship, Western Australia, 2004. -------------------------------------------   1000-1025  Target enzyme activity as biomarker for immunosuppression K. Budde, Berlin, Germany 1025-1055  Refreshment Break 1055-1210 Clinical impact of pharmacogenetics 1055-1120  CNI related nephrotoxicity: role of pharmacogenetics Dennis Hesselink, Rotterdam, Netherlands   1120-1145  Use of pharmacogenetics to optimise immunosuppressive therapy I.A. Macphee, London, UK   1145-1210  New directions for the pharmacogenetics of immunosuppressants Nicolas Picard , Limoges, France 1210-1340  Lunch 1340-1545 Clinical transplantation Chairs: David Holt, London, UK, and Les Shaw, Philadelphia, USA 1340-1405  Pediatric (liver and small bowel), and small intestinal transplant patients Raman Venkataramanan, Ph.D. Professor of Pharmaceutical Sciences and Pathology, University of Pittsburgh, Pittsburgh, USA Click here for Objectives of this presentation At the conclusion of this session the participant will be able to: • Understand the differences between small bowel transplant patients and other solid organ transplant patients in terms of immunosuppressive drug use; • Understand the differences in immunosuppressive drug dosing between adult and pediatric transplant patients; • Understand various approaches to optimize immunosuppression in these patient populations. ------------------------------------------- Click here: Raman Venkataramanan biography Raman Venkataramanan PhD Raman Venkataramanan is a Professor of Pharmaceutical sciences at the University of Pittsburgh School of Pharmacy. He also holds a joint appointment as a Professor of Pathology in the University of Pittsburgh School of Medicine. He is a member of the Thomas E. Starzl Transplantation Institute, the Center for Clinical Pharmacology, the molecular therapeutics and Drug Discovery program of the University of Pittsburgh Cancer Institute and McGowan Institute for Regenerative Medicine. He is the director of the Clinical Pharmacokinetics Laboratory at the University of Pittsburgh. He received his B.Pharm degree from University of Madras in Madras, India; M.Pharm. degree from BITS, Pilani, India, and Ph.D. from University of British Columbia, Vancouver, Canada. After a postdoctoral fellowship in the University of Washington, he joined the department of Pharmaceutical Sciences at the University of Pittsburgh in 1980. Dr. Venkataramanan is a fellow of the American College of Clinical Pharmacology and a fellow of the American Association of Pharmaceutical Scientists. He has been appointed as a Food and Drug Administration special government employee by the CDER. He serves as a scientific reviewer for several professional journals and organizations. He has been a reviewer for NCCAM, NIH and MRC. He is an editorial board member for the journals, Therapeutic Drug Monitoring and Journal of Clinical Pharmacology. He is the recipient of BMS Mentorship in Clinical Pharmacology (2009); Provost’s Award for Excellence in Graduate Education offered by the University of Pittsburgh (2009) and Innovations in Teaching offered by Rho Chi Society (2009). He has presented more than one hundred lectures/seminars at national and international meetings. He has published over 230 articles in peer-reviewed journals. He has been an active member in ITDMCT, AAPS, ACCP and AACC. The primary goal of his research has been to identify factors that regulate the pharmacokinetics and pharmacodynamics of drugs in organ transplant patients in order to optimize drug therapy in this patient population. He has contributed significantly to the development of cyclosporine and tacrolimus as immunosuppressive drugs. His current studies evaluate the effect of hepatic regeneration on the expression and activity of drug metabolizing enzymes and transporters and the clinical relevance of this in treating living donor liver transplant patients. Additional studies also address the role of ischemia reperfusion injury, inflammation, acute rejection, infection and immune modulation (cytokines/nitric oxide), ethnicity, hepatic regeneration and age on the pharmacokinetics of drugs. Evaluation of the functional aspect of the transplanted small intestine is an area of current research. Local delivery of drugs at the site of infection thereby avoiding systemic side effects is a theme that is being pursued in lung transplant patients. His group is also interested in studying the regulation of drug metabolism and transport during pregnancy and has initiated studies to evaluate developmental aspects of drug transporters such as P-glycoprotein (PgP) and drug metabolism. He has also conducted in vitro and in vivo studies to evaluate herb drug interactions. In addition to the clinical studies, his group uses in vitro systems (human hepatocyte cultures, microsomes, isolated organ perfusion systems) and animal (non-clinical) models to mechanistically understand the regulation of the various above processes. In particular, human hepatocyte culture system is used to evaluate the mechanism(s) of hepatotoxicity, drug-drug interactions, drug-herb interactions, drug-cytokine interactions. -------------------------------------------   1405-1430  Progress in pediatric kidney transplantation G. Filler, London, Canada   1430-1455  Progress in liver transplantation G. Levy, Toronto, Canada 1455-1520  Progress in kidney transplantation Paul A. Keown, MD, DSc, MBA, FACP, FASN, FRCP, FRCPC, FRCPath, FRSC, FIBiol, Professor of Medicine, Head of Nephrology, Director of Immunology, Chair, Regional Renal Program, University of British Columbia and Vancouver Coastal Health Authority, Vancouver, British Columbia, Canada   Click here: Paul Keown biography Paul A. Keown, MD, DSc, MBA, FACP, FASN, FRCP, FRCPC, FRCPath, FRSC, FIBiol Dr. Paul A. Keown is Professor of Medicine, Director of Immunology and Head of the Division of Nephrology at the University of British Columbia, with appointments in Medicine, Pathology and Laboratory Medicine. Dr. Keown graduated in Medicine from the University of Manchester, and pursued postgraduate training in England, France, and Canada. He holds research Doctorates in both Medicine and in Science from the University of Manchester, and an MBA from Simon Fraser University in British Columbia. Dr. Keown's research focuses particularly on the immune response in transplantation and autoimmune disease, and ranges from molecular genetics to healthcare economics. He is past Executive Director of the British Columbia Transplant Society, past president of the Canadian Transplant Society, a member of Council and Executive Committee of the Transplantation Society, and a member of numerous national and international scientific societies and professional organizations. He was elected a Fellow of: the Royal College of Physicians of Canada in 1977, the Royal College of Physicians of London in 1987, the American College of Physicians in 1994, the American Society of Nephrology and American Society of Angiology in 2008, and the Royal College of Pathologies and Royal Society of Chemistry in 2009. Dr. Keown is the founder and C.E.O. of Syreon Corporation, a global research corporation specializing in the use of advanced information technologies for health sciences research. ------------------------------------------- 1520-1545  Report of the MPA consensus meeting in Rome, Italy Dirk RJ Kuypers, Catholic University of Leuven, Leuven, Belgium Click here for Description of this presentation In this session a summary will be provided of the report of The Transplantation Society Consensus Meeting on Therapeutic Drug Monitoring of Mycophenolic Acid in solid organ transplantation, which was held in Rome, 20-21st November 2008, and involved forty-seven experts (physicians, pediatricians, surgeons, clinical pharmacologist and analytical experts) from around the world. The consensus report aimed at providing practical, evidence-based (irrespective of the level), information to clinicians who want to use MMF in a concentration-controlled way. This report focuses on the general, clinically relevant, pharmacokinetic properties of the drug, the association between drug exposure and efficacy and toxicity, the rational basis for clinically applied target therapeutic ranges, the different method for assessing drug exposure and finally the available analytical tools to measure MPA concentrations. ------------------------------------------- Click here for Objectives of this presentation At the conclusion of this session the participant will be able to: • Evaluate the different available strategies for measuring mycophenolic acid (MPA) exposure in solid organ transplant recipients in terms of clinical advantages and disadvantages; • Identify the currently advised target exposure ranges for MPA in the different types of solid organ transplantation; • Identify the relationship between MPA exposure and efficacy endpoints and adverse events in the different types of solid organ transplantation; • Identify the patients that could benefit from concentration-controlled dosing of MPA in the different types of solid organ transplantation. ------------------------------------------- Click here: Dirk RJ Kuypers biography Dirk RJ Kuypers MD Dirk RJ Kuypers completed his training as a medical doctor and subsequently as a consultant renal physician at the University Hospitals of the Catholic University of Leuven, Belgium. During his medical training he also worked in the Renal Department of Tygerberg Hospital, Capetown, Republic of South Africa. After his medical training he worked as a clinical transplant fellow in Westmead Hospital, Sydney, Australia. In 1998, he became full-time staff member in the Department of Nephrology and Renal Transplantation, University Hospitals Leuven. In 2004 he was appointed at the Catholic University of Leuven where he lectures on nephrology and evidence-based medicine. Fields of interest are mainly focused on transplantation medicine and pharmacology with a specific interest in immunosuppressive drug therapy and renal allograft surveillance using protocol biopsies. The topics of translational research focus on clinical pharmacokinetics, pharmacogenomics, personalized medicine, drug interactions and invasive and non-invasive (bio)markers of renal graft status. ------------------------------------------- 1545-1615  Refreshment Break 1615-1730 What’s new from Pharmaceutical industries 1615-1640  New tacrolimus granules formulation Nas Undre, Munich, Germany   1640-1705  New immunosuppressive drugs for transplantation: how deep is the pipeline? Teun van Gelder, Erasmus Medical Center, Rotterdam, The Netherlands Click here: Teun van Gelder biography Teun van Gelder Dr. Teun van Gelder was trained in internal medicine and nephrology at the Erasmus Medical Center in Rotterdam, the Netherlands. In 1996, he finished his thesis on the use of anti interleukin-2 receptor monoclonal antibodies in solid organ transplantation. As a post-doctoral scientist, he worked in the Transplantation Immunology Laboratory of Dr Randall E. Morris at Stanford University for two years. His current research at the Erasmus Medical Center is focused on clinical pharmacology and therapeutic drug monitoring. -------------------------------------------   1705-1730  Clinical pharmacokinetics of sotrastaurin (AEB071), a protein kinase C inhibitor John M. Kovarik, Senior Clinical Pharmacokineticist, Novartis Pharmaceuticals Basel, Switzerland Click here for Description of this presentation Sotrastaurin (AEB071) is an investigational immunosuppressant that blocks T-lymphocyte activation via protein kinase C inhibition. It is currently in phase 2 of clinical development for the prevention of acute rejection after solid organ transplantation and for the treatment of psoriasis. Sotrastaurin’s mechanism of action and its basic clinical pharmacokinetics in renal and liver transplant patients will be presented. Pharmacokinetic results from special population studies will demonstrate the impact of hepatic impairment, renal impairment, ethnicity, age, weight, and sex on sotrastaurin disposition. In vitro and clinical studies identifying the metabolic enzymes responsible for the biotransformation of sotrastaurin and the potential for drug interactions will be described. Clinical outcomes, T-cell inhibition biomarker data, and exposure-response relationships from phase 2 trials will show the clinical potential of sotrastaurin to prevent acute rejection and the possible role of therapeutic drug monitoring for this compound. ------------------------------------------- Click here for Objectives of this presentation • Compare sotrastaurin’s immunosuppressive mechanism of action with those of other immunosuppressants used in organ transplantation such as calcineurin inhibitors, proliferation signal inhibitors, and IL2-receptor blockers; • Identify the CYP enzymes for which sotrastaurin is a substrate and inhibitor in vitro. Based on these data and the pharmacokinetic results from clinical drug interaction studies performed to date, assess the potential for sotrastaurin to be a perpetrator and victim of pharmacokinetic drug interactions.; • 3. Whether therapeutic drug monitoring of sotrastaurin will be beneficial in organ transplantation has yet to be determined. Based on the bioanalytical, exposure, biomarker, and clinical response information generated to date in phase 2 trials, list data which potentially support sotrastaurin blood level monitoring and data that still need to be generated. ------------------------------------------- Click here: John Kovarik biography John M. Kovarik John M. Kovarik is a senior clinical pharmacokineticist at Novartis Pharmaceuticals based in Basel, Switzerland. He received the Novartis Leading Scientist award in 2004 for his work in exposure-response modeling and contributions to the drug development of the immunosuppressants ciclosporin, basiliximab, and everolimus for the prevention of acute rejection after organ transplantation. A Phi Beta Kappa and summa cum laude graduate of Macalester College (St Paul, MN, USA) majoring in chemistry, he went on to receive a Doctor of Pharmacy degree from the University of Minnesota, USA and a PhD from the Royal University of Utrecht, the Netherlands. Dr Kovarik has authored over 100 scientific articles and book chapters and over 75 congress abstracts. He is cited in Who’s Who in Medicine and Health Care and Who’s Who in the World and serves on the editorial board and/or as reviewer of several pharmacology journals. -------------------------------------------   1730  Wrap up 1745  Closing Remarks

 

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