OBJECTIVES. Phases of Transplantation and Immunosuppression

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1 Transplant and Immunosuppression: Texas Transplant Center April 29, 2017 Regina L. Ramirez, Pharm.D., BCPS PGY1 Pharmacy Residency Program Director Clinical Practice Specialist Solid Organ Transplant and VAD Programs Department of Pharmacy UTMB Health 1 OBJECTIVES Identify phases of solid organ transplantation Identify different types of medications used in solid organ transplantation Discuss toxicities of transplant immunosuppression Briefly discuss new medications under review/investigation for solid organ transplantation 2 Phases of Transplantation and Immunosuppression 3 1

2 OVERVIEW Induction ratg Alemtuzumab Basiliximab Corticosteroids Maintenance CNIs Antiproliferative Corticosteroids mtor Inhibitors T-cell Costimulation Blocker Rejection IVIG Preparations Bortezomib Rituximab Eculizumab ratg: antithymocyte globulin, rabbit CNI: calcineurin inhibitor mtor: mammalian target of rapamycin IVIG: immune globulin 4 HISTORY 1954 First successful kidney transplant 1967 First successful liver transplant 1968 First successful heart transplant 1983 Cyclosporine introduced First successful single lung transplant Cupples A & Ohler L. (2002). Solid Organ Transplantation: A Handbook for Primary Health Care Providers. New York, NY:Springer Publishing Company, Inc. 5 TIMELINE 6 2

3 TIMELINE Kahan B. Nature Reviews Immunology 2003;3: Transplant and Immunosuppression: 8 PAST IMMUNOSUPPRESSANTS Azathioprine Bone marrow suppression Thrombocytopenia Prednisone Hypertension Hyperglycemia Weight gain Infection Low bone density 9 3

4 Transplant and Immunosuppression: 10 Alemtuzumab Fever/Chills/Rigors Increased risk for infections Bone marrow suppression Immune thrombocytopenic purpura ratg Serum sickness Fever/Chills/Rash Urticaria /thrombocytopenia Increased risk for infections PTLD ratg: antithymocyte globulin, rabbit PTLD: post-transplant lymphoproliferative disease 11 Cyclosporine Nephrotoxicity/Neurotoxicity Hypertension/Hyperglycemia Electrolyte abnormalities Histopathologic changes Hirsutism Gingival hyperplasia Tacrolimus Nephrotoxicity/Neurotoxicity Hypertension/Hyperglycemia Electrolyte abnormalities Hyperuricemia PTLD PTLD: post-transplant lymphoproliferative disease 12 4

5 Mycophenolate Nausea Diarrhea Abdominal discomfort Infection (CMV) Azathioprine Thrombocytopenia Hepatotoxicity Drug interactions CMV: cytomegalovirus 13 Sirolimus Everolimus Cytopenias Hyperlipidemia Impaired wound healing Mouth ulcers Proteinuria Cytopenias Peripheral edema Impaired wound healing Mouth ulcers 14 Belatacept and Long-term Outcomes Purpose Summarize efficacy and safety results up to 7 years after transplantation Methods Randomly assigned kidney transplant recipients Less-intensive vs. more-intensive vs. cyclosporine Primary objective Composite: patient/graft survival, renal function, rejection Results Risk of death or graft loss: 43% reduction Mean egfr increased over 7-year period Conclusion Patient/graft survival and mean egfr were significantly higher in belatacept versus cyclosporine recipients egfr: estimated glomerular filtration rate Vicenti F, et al. N Engl J Med 2016;374:

6 Transplant and Immunosuppression: 16 FUTURE IMMUNOSUPPRESSANTS Eculizumab for Antibody-mediated Rejection Purpose Eculizumab would stabilize graft function in de novo DSA patients Methods Randomized controlled trial Adult kidney transplant recipients with DSAs > 1100 MFI Primary objective Difference in percentage change of egfr trajectory MFI: mean fluorescence intensity Kulkarni S, et al. Am J Transplant 2017;17: FUTURE IMMUNOSUPPRESSANTS Eculizumab for Antibody-mediated Rejection Results Conclusion Six months of eculizumab treatment provided stabilization of renal function compared to the control group Kulkarni S, et al. Am J Transplant 2017;17:

7 FUTURE IMMUNOSUPPRESSANTS Complement inhibition Eculizumab Calcineurin inhibitors Voclosporine Janus kinase (JAK) inhibition Tofracitinib IL-6 inhibition Tocilizumab Interference with CD2 and LFA-3 Alefacept Protein kinase C inhibition Sotrastaurin IL: interleukin CD: cluster of differentiation LFA: lymphocyte function-associated antigen Wiseman A. Clin J Am Soc Nephrol 2015;1-10. Weaver T, et al. Nat Med 2009;15: Friman S, et al. Am J Transplant 2011:11: Transplant and Immunosuppression: Texas Transplant Center April 29, 2017 Regina L. Ramirez, Pharm.D., BCPS PGY1 Pharmacy Residency Program Director Clinical Practice Specialist Solid Organ Transplant and VAD Programs Department of Pharmacy UTMB Health rlramire@utmb.edu 20 7