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Personalized Immunosuppression in Transplantation

Role of Biomarker Monitoring and Therapeutic Drug Monitoring

1st Edition - August 8, 2015

Editors: Michael Oellerich, Amitava Dasgupta

Hardback ISBN:

9 7 8 - 0 - 1 2 - 8 0 0 8 8 5 - 0

eBook ISBN:

9 7 8 - 0 - 1 2 - 8 0 1 1 3 3 - 1

Personalized Immunosuppression in Transplantation: Role of Biomarker Monitoring and Therapeutic Drug Monitoring provides coverage of the various approaches to monitoring… Read more

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Personalized Immunosuppression in Transplantation: Role of Biomarker Monitoring and Therapeutic Drug Monitoring

provides coverage of the various approaches to monitoring immunosuppressants in transplant patients, including the most recently developed biomarker monitoring methods, pharmacogenomics approaches, and traditional therapeutic drug monitoring.

The book is written for pathologists, toxicologists, and transplant surgeons who are involved in the management of transplant patients, offering them in-depth coverage of the management of immunosuppressant therapy in transplant patients with the goal of maximum benefit from drug therapy and minimal risk of drug toxicity.

This book also provides practical guidelines for managing immunosuppressant therapy, including the therapeutic ranges of various immunosuppressants, the pitfalls of methodologies used for determination of these immunosuppressants in whole blood or plasma, appropriate pharmacogenomics testing for organ transplant recipients, and when biomarker monitoring could be helpful.

Preface
List of Contributors
Chapter 1. Overview of the pharmacology and toxicology of immunosuppressant agents that require therapeutic drug monitoring
- 1.1 Introduction
- 1.2 Calcineurin Inhibitors
- 1.3 Antimetabolite Drug
- 1.4 Mammalian Target of Rapamycin Inhibitors
- 1.5 Conclusions
- References
Chapter 2. Limitations of immunoassays used for therapeutic drug monitoring of immunosuppressants
- 2.1 Introduction
- 2.2 Methods for Therapeutic Drug Monitoring of Immunosuppressants
- 2.3 Cyclosporine Monitoring: Trough or C2 Monitoring?
- 2.4 Limitations of Immunoassays Used for Cyclosporine Monitoring
- 2.5 Limitations of Immunoassays Used for Tacrolimus Monitoring
- 2.6 Limitations of Immunoassays Used for Sirolimus Monitoring
- 2.7 Limitations of Immunoassays Used for Everolimus Monitoring
- 2.8 Limitations of Immunoassays Used for Mycophenolic Acid Monitoring
- 2.9 Conclusions
- References
Chapter 3. Application of liquid chromatography combined with mass spectrometry or tandem mass spectrometry for therapeutic drug monitoring of immunosuppressants
- 3.1 Introduction
- 3.2 Evolution of Non-Immunoassay Methods for Immunosuppressants
- 3.3 LC–MS/MS Methods for Analysis of Immunosuppressants
- 3.4 Limitation of Mass Spectrometric Methods
- 3.5 Turnaround Time
- 3.6 Conclusions
- References
Chapter 4. Monitoring free mycophenolic acid concentration: Is there any clinical advantage?
- 4.1 Introduction
- 4.2 Monitoring Free Drug Concentration
- 4.3 Monitoring Free (Unbound) Fraction of Cyclosporine
- 4.4 Monitoring Free (Unbound) Fraction of Tacrolimus and Sirolimus
- 4.5 Mycophenolic Acid: A Brief Introduction
- 4.6 Rationale for Therapeutic Drug Monitoring of Mycophenolic Acid
- 4.7 Conclusion
- References
Chapter 5. Pharmacogenomics aspect of immunosuppressant therapy
- 5.1 Introduction
- 5.2 Individual Genes
- 5.3 Conclusions
- References
Chapter 6. Biomarker monitoring in immunosuppressant therapy: An overview
- 6.1 Introduction
- 6.2 Current Immunosuppressive Agents and Their Effects on Immune Responsiveness
- 6.3 Biomarkers to Guide Immunosuppressant Therapy
- 6.4 Calcineurin Phosphate
- 6.5 Nuclear Factor of Activated T Lymphocytes Regulated Gene Expression
- 6.6 Inosine Monophosphate Dehydrogenase
- 6.7 Phosphorylation of mTOR Downstream Effectors
- 6.8 Pharmacogenetic Biomarkers
- 6.9 Biomarkers Nonspecific for Single Drug Action
- 6.10 Conclusions
- References
Chapter 7. Graft-derived cell-free DNA as a marker of graft integrity after transplantation
- 7.1 Introduction
- 7.2 Causes of Chronic Allograft Dysfunction
- 7.3 Need for Biomarkers
- 7.4 Value of Conventional TDM
- 7.5 Biomarkers for Immune Monitoring as Supplement to TDM
- 7.6 Molecular Methods: Biopsy and Cellular Approaches
- 7.7 Conclusions
- Acknowledgments
- References
Chapter 8. Biomarkers of tolerance in kidney transplantation
- 8.1 Introduction
- 8.2 Definition of the Clinical Status of Operational Tolerance
- 8.3 Technical Considerations on the Biodetection of Tolerance
- 8.4 A B-Cell Signature Predominates in Blood from Tolerant Recipients
- 8.5 An Unsuspected Role for B Cell in Operational Tolerance
- 8.6 Potential Applications of the Biomarkers and the Future for Tolerance Research
- 8.7 Conclusions
- References
Chapter 9. Intracellular concentrations of immunosuppressants
- 9.1 Introduction
- 9.2 Measuring Intracellular Concentrations of Immunosuppressants
- 9.3 Immunosuppressant Drug Concentrations in PBMCs/Lymphocytes
- 9.4 Drug Transport Across Lymphocyte Cell Membranes: The Role of P-Glycoprotein
- 9.5 Considerations Regarding Intracellular Drug Monitoring
- 9.6 Conclusions
- References
Chapter 10. Markers of lymphocyte activation and proliferation
- 10.1 Introduction
- 10.2 Lymphocyte Proliferation and Activation in Allograft Rejection
- 10.3 Effect of Immunosuppressants on Lymphocyte Proliferation and Activation
- 10.4 Conclusions
- References
Chapter 11. Monitoring calcineurin inhibitors response based on NFAT-regulated gene expression
- 11.1 Introduction
- 11.2 Mechanism of Action of CNIs
- 11.3 Strategies for Pharmacodynamic Monitoring of CNIs
- 11.4 Measurement of NFAT-Regulated Gene Expression
- 11.5 Molecular Response to CNI Exposure
- 11.6 CNI Pharmacodynamics and Clinical Outcome
- 11.7 Perspectives
- 11.8 Conclusions
- References
Index

Michael Oellerich

Michael Oellerich, MD, HonMD, FACB, FAMM, FFPath (RCPI), FRCPath, is a chemical pathologist. Since 2012, he has had an appointment as a Lower Saxony Distinguished Professor of Clinical Chemistry at the Department of Clinical Pharmacology, Medical Faculty (UMG) of the George-August University, Göttingen, Germany. He was Chairman of the Department of Clinical Chemistry/Central Laboratory at UMG from 1991 to 2012. Since 2013, he has been a member of the Medical Advisory Board of Chronix Biomedical Inc., San Jose, CA, USA. From 1996 to 1998, he served as Dean of the Faculty of Medicine. He also served as President of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), the German Association for Laboratory Medicine, the German United Association for Clinical Chemistry and Laboratory Medicine, and the World Association of Societies of Pathology and Laboratory (WASPaLM). Since 2003, he has been Editor-in-Chief of Therapeutic Drug Monitoring. Previously, he was Associate Editor of Clinical Biochemistry and of Clinical Chemistry. His current research interests are in the field of therapeutic drug monitoring, with particular focus on endogenous biomarkers to achieve personalized immunosuppression in transplantation (e.g. graft-derived circulating cell-free DNA as “liquid biopsy”), as well as pharmacogenetics. Further topics include proteomics, analytical techniques (e.g. LC-MS/MS), and molecular diagnostics. He has authored more than 400 publications, and has received various awards (e.g. Ludolf-Krehl Award, IATDMCT Charles Pippenger Award, WASPaLM Medal of Honor, WASPaLM Gold-Headed Cane).

Affiliations and expertise

Lower Saxony Distinguished Professor of Clinical Chemistry, George-August University, University Medical Center Göttingen, Department of Clinical Pharmacology, Göttingen, Germany

Amitava Dasgupta

Dr. Amitava Dasgupta received his Ph.D degree in Chemistry from Stanford University and received his medical training in Toxicology and Clinical Chemistry from the Laboratory Medicine Department of the University of Washington School Of Medicine at Seattle. He is board certified in both Toxicology and Clinical Chemistry by the American Board of Clinical Chemistry. He is a tenured Full Professor of Pathology and Laboratory Medicine at the University of Texas Health Sciences Center located at the Texas Medical Center at Houston. He is also the Director of Clinical Chemistry and Toxicology Laboratory of Memorial-Hermann Laboratory Services, the major clinical teaching hospital of the University of Texas. In addition, he is also the Medical Director of Memorial-TIRR Hospital laboratory services.

Dr. Dasgupta has published over 235 scientific papers and edited, co-edited, authored or co-authored 20 books including books published by Elsevier. He is on the Editorial Board of five major medical journals including American Journal of Clinical Pathology, Archives of Pathology and Laboratory Medicine, Therapeutic Drug Monitoring, Clinica Chimica Acta and Journal of Clinical Laboratory Analysis. He lectures both nationally and internationally on drug and alcohol testing and acts as an expert witness for the State of Texas for alcohol and drug related criminal prosecutions.

Affiliations and expertise

Dept. Pathology and Laboratory Medicine, UTHealth, Houston, USA