Personalized immunosuppression in transplantation : role of biomarker monitoring and therapeutic drug monitoring / edited by Michael Oellerich, MD and Amitava Dasgupta, PhD.

Format:

Book

Contributor:

Oellerich, Michael, editor.

DasGupta, A. (Amitava), editor.

ScienceDirect (Online service)

Patrick B. and Anne Gaydosh Hughes Memorial Book Fund.

Language:

English

Subjects (All):

Immunosuppressive agents.

Transplantation immunology.

Drug monitoring.

Biochemical markers.

Immunosuppressive Agents--therapeutic use.

Transplantation Immunology.

Medical Subjects:

Immunosuppressive Agents--therapeutic use.

Transplantation Immunology.

Physical Description:

1 online resource (xiv, 302 pages.)

Place of Publication:

Amsterdam, Netherlands ; Waltham, MA, USA : Elsevier, [2016]

System Details:

text file

Summary:

Personalized Immunosuppression in Transplantation provides in-depth 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. It 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 pharmacogenotics testing for organ transplant recipients, and guidelines for when biomarker monitoring can be helpful. This is essential reading for pathologists and toxicologists involved in the therapeutic drug monitoring of immunosuppressants, along with transplant clinicians and surgeons involved the individual care of transplant patients. Book jacket.

Contents:

Chapter 1 Overview of the Pharmacology and Toxicology of Immunosuppressant Agents that Require Therapeutic Drug Monitoring / Michael C. Milone Milone, Michael C. 1

1.1 Introduction 1

1.2 Calcineurin Inhibitors 2

1.2.1 Cyclosporine A 2

1.2.2 Tacrolimus 7

1.3 Antimetabolite Drug 10

1.4 Mammalian Target of Rapamycin Inhibitors 13

1.4.1 Sirolimus (Rapamycin) 13

1.4.2 Everolimus (RAD001) 18

1.5 Conclusions 19

References 19

Chapter 2 Limitations of Immunoassays Used For Therapeutic Drug Monitoring of Immunosuppressants / Amitava Dasgupta Dasgupta, Amitava 29

2.1 Introduction 29

2.2 Methods for Therapeutic Drug Monitoring of Immunosuppressants 31

2.3 Cyclosporine Monitoring: Trough or C2 Monitoring? 34

2.4 Limitations of Immunoassays Used for Cyclosporine Monitoring 35

2.5 Limitations of Immunoassays Used for Tacrolimus Monitoring 38

2.6 Limitations of Immunoassays Used for Sirolimus Monitoring 43

2.7 Limitations of Immunoassays Used for Everolimus Monitoring 45

2.8 Limitations of Immunoassays Used for Mycophenolic Acid Monitoring 48

2.9 Conclusions 51

References 51

Chapter 3 Application of Liquid Chromatography Combined with Mass Spectrometry or Tandem Mass Spectrometry For Therapeutic Drug Monitoring of Immunosuppressants / Kamisha L. Johnson-Davis Johnson-Davis, Kamisha L., Gwendolyn A. McMillin McMillin, Gwendolyn A. 57

3.1 Introduction 57

3.2 Evolution of Non-Immunoassay Methods for Immunosuppressants 59

3.3 LC-MS/MS Methods for Analysis of Immunosuppressants 60

3.3.1 Preanalytical Variable: Specimens 63

3.3.2 Preanalytical Variable: Specimen Collection 64

3.3.3 Preanalytical Variable: Drug-Drug Interactions 64

3.3.4 Preanalytical Variable: Genetic Polymorphisms 65

3.3.5 Preanalytical Variable: Clinical Status of the Patient 66

3.3.6 Preanalytical Variable: Pregnancy 66

3.3.7 Analytical Step: Specimen Preparation 67

3.3.8 Analytical Step: Reagents 68

3.3.9 Analytical Step: Solvents 69

3.4 Limitation of Mass Spectrometric Methods 70

3.4.1 Ion Suppression/Enhancement 72

3.5 Turnaround Time 74

3.6 Conclusions 74

References 75

Chapter 4 Monitoring Free Mycophenolic Acid Concentration: Is There Any Clinical Advantage? / Amitava Dasgupta Dasgupta, Amitava 83

4.1 Introduction 83

4.2 Monitoring Free Drug Concentration 84

4.3 Monitoring Free (Unbound) Fraction of Cyclosporine 86

4.4 Monitoring Free (Unbound) Fraction of Tacrolimus and Sirolimus 88

4.5 Mycophenolic Acid: A Brief Introduction 89

4.6 Rationale for Therapeutic Drug Monitoring of Mycophenolic Acid 91

4.6.1 Serum Protein Binding of Mycophenolic Acid 92

4.6.2 Conditions That Increase Free Mycophenolic Acid Level 93

4.6.3 Clinical Utility of Monitoring Free Mycophenolic Acid 98

4.6.4 Drug-Mycophenolic Acid Interaction 99

4.6.5 Analytical Methods for Determination of Free Mycophenolic Acid 101

4.7 Conclusion 103

References 103

Chapter 5 Pharmacogenomics Aspect of Immunosuppressant Therapy / Laralie Langman Langman, Laralie, Teun van Gelder Gelder, Teun van, Ron H.N. van Schaik Schaik, Ron H.N. van 109

5.1 Introduction 109

5.2 Individual Genes 109

5.2.1 Cytochrome P450 110

5.2.2 POR 113

5.2.3 ABCB1 114

5.2.4 UGT1A9 116

5.2.5 Other Genetic Factors 117

5.3 Conclusions 118

References 118

Chapter 6 Biomarker Monitoring in Immunosuppressant Therapy: An Overview / Maria Shipkova Shipkova, Maria 125

6.1 Introduction 125

6.2 Current Immunosuppressive Agents and Their Effects on Immune Responsiveness 127

6.3 Biomarkers to Guide Immunosuppressant Therapy 127

6.4 Caleineurin Phosphate 130

6.5 Nuclear Factor of Activated T Lymphocytes Regulated Gene Expression 130

6.6 Inosine Monophosphate Dehydrogenase 131

6.7 Phosphorylation of mTOR Downstream Effectors 133

6.8 Pharmacogenetic Biomarkers 134

6.9 Biomarkers Nonspecific for Single Drug Action 135

6.9.1 Biomarkers of Organ Damage 135

6.9.2 Biomarkers of Immune Response 137

6.9.3 Molecules Involved in Cytotoxicity 142

6.9.4 Biomarkers of Tolerance 142

6.10 Conclusions 143

References 144

Chapter 7 Graft-Derived Cell-Free DNA as a Marker of Graft Integrity After Transplantation / Michael Oellerich Oellerich, Michael, Julia Beck Beck, Julia, Philipp Kanzow Kanzow, Philipp, Jessica Schmitz Schmitz, Jessica, Otto Kollmar Kollmar, Otto, Philip D. Walson Walson, Philip D., Ekkehard Schütz Schütz, Ekkehard 153

7.1 Introduction 153

7.2 Causes of Chronic Allograft Dysfunction 154

7.3 Need for Biomarkers 154

7.4 Value of Conventional TDM 155

7.4.1 Limitations of TDM 155

7.5 Biomarkers for Immune Monitoring as Supplement to TDM 156

7.5.1 Minimization of ISD Exposure and Assessment of Graft Function 157

7.6 Molecular Methods: Biopsy and Cellular Approaches 158

7.6.1 Cell-Free Molecular Methods 159

7.6.2 GcfDNA Limitations 170

7.7 Conclusions 171

Acknowledgments 172

References 172

Chapter 8 Biomarkers of Tolerance in Kidney Transplantation / Daniel Baron Baron, Daniel, Magali Giral Giral, Magali, Sophie Brouard Brouard, Sophie 177

8.1 Introduction 177

8.2 Definition of the Clinical Status of Operational Tolerance 178

8.3 Technical Considerations on the Biodetection of Tolerance 179

8.3.1 Biomarkers and Limits of Conventional Tests 179

8.3.2 Choice of Technology 180

8.3.3 Choice of Specimen 180

8.3.4 Choice of Control 181

8.4 A B-Cell Signature Predominates in Blood from Tolerant Recipients 181

8.4.1 Tolerant Patients Overexpress B-Cell Biomarkers 182

8.4.2 Tolerant Patients Expand Specific B-Cell Subsets 182

8.5 An Unsuspected Role for B Cell in Operational Tolerance 183

8.6 Potential Applications of the Biomarkers and the Future for Tolerance Research 185

8.6.1 Personalized Minimization of Immunosuppressant Therapy 186

8.6.2 Permissive B-Cell Therapies to Induce Tolerance 187

8.7 Conclusions 188

References 189

Chapter 9 Intracellular Concentrations of Immunosuppressants / Heike Bittersohl Bittersohl, Heike, Werner Steimer Steimer, Werner 199

9.1 Introduction 199

9.2 Measuring Intracellular Concentrations of Immunosuppressants 200

9.2.1 Analytical Techniques 200

9.3 Immunosuppressant Drug Concentrations in PBMCs/Lymphocytes 203

9.3.1 Cyclosporine A 203

9.3.2 Tacrolimus 206

9.3.3 Mycophenolic Acid 210

9.3.4 PSIs: Sirolimus and Everolimus 210

9.4 Drug Transport Across Lymphocyte Cell Membranes: The Role of P-Glycoprotein 212

9.4.1 Modifiers of P-gp Activity 212

9.4.2 The Genetics of P-gp (ABCB1) 213

9.5 Considerations Regarding Intracellular Drug Monitoring 215

9.5.1 Drug Binding Proteins in the Lymphocyte Cytoplasm 216

9.5.2 Lymphocyte Intrapalient Variation of White Blood Cells 217

9.6 Conclusions 219

References 220

Chapter 10 Markers of Lymphocyte Activation and Proliferation / Eberhard Wieland Wieland, Eberhard 227

10.1 Introduction 227

10.2 Lymphocyte Proliferation and Activation in Allograft Rejection 228

10.3 Effect of Immunosuppressants on Lymphocyte Proliferation and Activation 230

10.3.1 Cell Function Tests and T-Cell Activation in Whole Blood 230

10.3.2 Analytical Techniques to Assess Lymphocyte Activation and Proliferation 231

10.3.3 Soluble Lymphocyte Surface Molecules in Plasma or Serum 240

10.3.4 Cytokines 241

10.3.5 Assay Performance 246

10.4 Conclusions 248

References 249

Chapter 11 Monitoring Calcineurin Inhibitors Response Based on NFAT-Regulated Gene Expression / Sara Bremer Bremer, Sara, Nils Tore Vethe Vethe, Nils Tore, Stein Bergan Bergan, Stein 259

11.1 Introduction 259

11.2 Mechanism of Action of CNIs 260

11.2.1 Activation of the Calcineurin-NFAT Signaling in T Cells 260

11.2.2 CNI Effects in Immune Cells 260

11.2.3 Effects of CNI on Non-Immune Cells 263

11.2.4 Differences between Cyclosporine and Tacrolimus 264

11.3 Strategies for Pharmacodynamic Monitoring of CNIs 264

11.3.1 Calcineurin Phosphatase Activity 264

11.3.2 Nuclear Translocation of NFAT 265

11.3.3 Cytokine Responses 265

11.4 Measurement of NEAT-Regulated Gene Expression 266

11.4.1 Specimen 267

11.4.2 Sampling Time Point 267

11.4.3 Ex Vivo Stimulation with Mitogens 267

11.4.4 RT and qPCR 268

11.4.5 Extraction of RNA and RT 268

11.4.6 Real-Time PCR 269

11.4.7 Relative Quantification of Gene Expression 269

11.4.8 Residual Gene Expression 270

11.4.9 Assay Validation 271

11.4.10 Assay Specificity 271

11.5 Molecular Response to CNI Exposure 272

11.5.1 Differences in Molecular Responses of Tacrolimus and Cyclosporine 273

11.5.2 Interindividual Variability in Molecular CNI Responses 273

11.5.3 Intraindividual Variability in Molecular CNI Responses 281

11.6 CNI Pharmacodynamics and Clinical Outcome 281

11.7 Perspectives 283

11.8 Conclusions 285

References 285.

Notes:

Includes bibliographical references and index.

Electronic reproduction. Amsterdam Available via World Wide Web.

Description based on print version record.

Local Notes:

Acquired for the Penn Libraries with assistance from the Patrick B. and Anne Gaydosh Hughes Memorial Book Fund.

ISBN:

9780128011331

0128011335

Publisher Number:

99964435449

Access Restriction:

Restricted for use by site license.