10/4/18 Objectives PHARMACIST TECHNICIAN Kidney Transplantation: • Describe mechanisms of • Identify medications used transplant in transplant recipients What Pharmacists & Technicians immunosuppression • Identify common adverse • Outline documentation Need to Know effects to transplant requirements for Amanda J. Condon, PharmD, BCPS immunosuppression transplant medications Solid Organ Transplant Pharmacist • Modify transplant University of New Mexico Hospitals regimens to ensure safety and efficacy 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 1 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 2 Epidemiology – U.S. Epidemiology – New Mexico 95,124 13,992 24,213 522 52 2,310 people need lifesaving kidney kidney transplants have been Donors recovered so far in people need lifesaving kidney kidney transplants have been Patients have been transplanted transplants (total waitlist performed so far in 2018 2018 transplants in New Mexico performed in New Mexico since 1988 candidates) (January to August 2018) (January to August 2018) 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 3 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 4 Epidemiology Indications for Transplant Modifiable • Diabetes • Hypertension • NSAID overuse Non-Modifiable • Genetics (polycystic kidney disease, etc) • Congenital Abnormalities (obstructive uropathy, etc) • Glomerular Disease (anti-GBM, IgA Nephropathy, etc) 10/4/18 NMSHP: KIDNEYhttps://optn.transplant.hrsa.gov/ TRANSPLANTATION 5 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 6 1 10/4/18 Transplant Course Goals oF Immunosuppression Infection Rejection Malignancy Monthly Adherence (ACR vs AMR) Weekly Visits Visits Toxicity Listing Transplant! ~ 1 month ~ 6 months Pre- Waiting on List Biweekly Bimonthly q6-12 month Transplant ~ Months to Years Visits Visits Visits Graft Work Up ~ 1 month ~ 3 months ..Forever Patient & ~6 mos – 1 year Failure Graft Survival 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 7 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 8 Sensitization & Risk Factors For Rejection Phases of Immunosuppression Transplant Rejection HLA DCD Organ Sensitizing Mismatch Delayed Risk Factors Events Previous Graft Transplant Function Blood Rejection Transfusion Episodes Induction Previous Graft African Pregnancy Loss American Desensitization Maintenance 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 9 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 10 Determination oF Regimens Induction Agents • Evaluation of Immunologic Risk Goal: To prevent early acute allograft rejection immediately • HLA mismatch • Blood group post-transplant using intense, prophylactic • Younger recipient and incompatibility immunosuppressive therapy older donor • Delayed onset of graft • African-American function (DGF) – Basiliximab (Simulect®) • Panel Reactive Antibody • Cold ischemia time > 24 ◦ 20 mg IV POD0 and POD4 (PRA) > 0 hours • Donor-specific Antibody – Antithymocyte Globulin (Thymoglobulin®) (DSA) ◦ 2 mg/kg (IBW) IV starting POD0 up to 6mg/kg total • Evaluation of Infectious Risk • Elderly • Previous chemotherapy – Alemtuzumab (Campath®) • HBV exposure • ganR CMV ◦ 30 mg IV POD0 • HCV exposure 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 11 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 12 2 10/4/18 Basiliximab (Simulect®) • Mechanism of Action: – Blocks T-cell proliferation via Interleukin-2 (IL-2) receptor antagonism (anti-CD25 antibodies) • Used in lowest immunologic risk patients • Decreased infection rates when compared to thymoglobulin • Does not lead to sustained depletion of lymphocytes and related CD4 helper T cells N Engl J Med. 2004 Dec 23;351(26):2715-29. 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 13 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 14 Antithymocyte Globulin Antithymocyte Globulin (Thymoglobulin®) (Thymoglobulin®) • Mechanism of Action: • Infusion reactions common – Binds to T-cell surface antigens leading to the elimination of T-cells – Associated with previous rabbit exposure – Premedicate: APAP 650mg PO, Benadryl 25mg IV, Steroids • Used in moderate to high immunologic risk patients • Can cause serum sickness • Increased risk for CMV and BKV – Occurs 10-21 days after administration • PJP and other invasive fungal pathogens have been associated with – Presentation: Myalgias, fever, fatigue, jaw pain thymoglobulin • Monitoring: – WBC, Platelets – Reduction if WBC < 3 or PLT < 75 – Hold if WBC < 2 or PLT < 50 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 15 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 16 Alemtuzumab (Campath®) Phases of Immunosuppression • Mechanism of Action: Transplant Rejection – Binds to CD52 on T-cells, B-cells, NK cells, and monocytes/macrophages causing complement activation and antibody-dependent cellular toxicity • “AIDS” in a bottle that can result in pan-T-cell depletion • CD4/CD8 counts nadir at 4 weeks, 1 year for recovery • Associated with many opportunistic infections Induction Desensitization Maintenance 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 17 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 18 3 10/4/18 Maintenance Agents Goal: To prevent early and late allograft rejection post- transplant using long-term prophylactic immunosuppressive therapy • Corticosteroids • CTLA-4 Blockade (Belatacept) (Methylprednisolone, Prednisone) • mTOR Inhibitors (Sirolimus, • Calcineurin Inhibitors (Tacrolimus, Everolimus) Cyclosporine) • Antimetabolites (Mycophenolate, Azathioprine) N Engl J Med. 2004 Dec 23;351(26):2715-29. 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 19 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 20 Corticosteroids (Prednisone, Corticosteroids (Prednisone, Methylprednisolone) Methylprednisolone) • Mechanism of Action: •Adverse Effects….. are plenty – Profound immune system augmentation including inhibition of IL-1, 2, 3, 4, 5, 6, 8, TNF involved in T-cell proliferation; decreased B-cell SHORT TERM LONG TERM clone expansion, and decreased antibody synthesis • Mood Change • Osteoporosis • Increased risk of bacterial, mycobacterial, viral and fungal infections • Hyperglycemia* • Adrenal Insufficiency • Hypertension* • Ulcerative Esophagitis • Routinely used to treat rejection • Increased Appetite • Hirsutism • Insomnia • Pacreatitis • Acne • Amenorrhea • Leukocytosis* • Diabetes Mellitus 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 21 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 22 Calcineurin Inhibitors (Tacrolimus, Calcineurin Inhibitors (Tacrolimus, Cyclosporine) Cyclosporine) • Mechanism of Action: – Binds to immunophilins and block the function of calcineurin at different enzymatic sites, resulting in downstream impairment of T-cell IL-2 synthesis • Tacrolimus is broader in inhibitory effect (IL-3, IL-4, IL-5, IFN-γ, other cytokines) • CsA has antiviral properties – HIV, HSV, HCV • Increased risk of CMV and BKV 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 23 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 24 4 10/4/18 Calcineurin Inhibitors (Tacrolimus, Calcineurin Inhibitors (Tacrolimus, Cyclosporine) Cyclosporine) • Drug Interactions GUT – Primarily through hepatic metabolism (CYP3A4 inhibition or induction) ◦ ↑ Drug Level: ketoconazole, diltiazem, fluconazole, grapefruit juice ◦ ↓ Drug Level: phenytoin, rifampin – P-gp Substrate – Drug interactions have high inter- and intra-patient variability – Consistent administration with or without food BLOOD 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 25 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 26 When to Check Troughs? Tacrolimus Preparations • Depends on the clinical situation and when last trough was checked • Prograf – Immediate release capsule • Recommend erring on side of caution and checking a trough when in doubt – IV preparation ◦ Dose reduce to 1/3 of oral dose as a continuous infusion • Any AKI ◦ Please don’t do this – use sublingual instead (if possible) – Tacrolimus can be the cause of AKI – Can be used for SL administration – Tacrolimus is NOT renally excreted ◦ Dose reduce 1 mg PO : 0.5 mg SL • Any diarrhea • Astagraf – Tacrolimus levels are increased during episodes of diarrhea – Once-daily long-acting capsule – Really only used for tacrolimus-sensitive patients (ie, 0.5mg once a day = 0.25mg Prograf BID) 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 27 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 28 Calcineurin Inhibitors (Tacrolimus, Tacrolimus Preparations Cyclosporine) • Envarsus XR • Tacrolimus Adverse Effects – Once-daily long-acting tablet – Fantastic pharmacokinetics! • Hypertension • Hyperglycemia* – Significantly less neurotoxicity • Diarrhea • Pruritis • Nephrotoxicity • Hyperkalemia • Headache • Hypomagnesemia • Hepatotoxicity • Infection • Neurotoxicity • Alopecia 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 29 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 30 5 10/4/18 Calcineurin Inhibitors (Tacrolimus, Calcineurin Inhibitors (Tacrolimus, Cyclosporine) Cyclosporine) • Cyclosporine Adverse Effects • Adverse Effects Tacrolimus Cyclosporine LESS COMMON MORE COMMON Nephrotoxicity +++ ++ • Migraine • Hyperlipidemia Hyperglycemia & DM +++ ++ • • Nephrotoxicity Acne Neurotoxicity +++ ++ • GI effects • Tremor Electrolyte abnormalities +++ ++ • Gynecomastia • Hypertension • • Hyperkalemia Hyperglycemia Hypertension +++ +++ • Gingival hyperplasia • Hypomagnesemia Other Alopecia Hirsutism, • • Hepatotoxicity Hirsutism hyperlipidemia, gingival hyperplasia, hyperuricemia 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 31 10/4/18 NMSHP: KIDNEY TRANSPLANTATION 32 Antimetabolites (Mycophenolate, Antimetabolites (Mycophenolate, Azathioprine) Azathioprine) • Mechanism of Action: – Targets enzymes involved in de novo synthesis of purines leading to impairment of DNA replication in B- and T-cells • Potential for bone marrow suppression • Significantly increased risk for major viral, fungal and parasitic infections • Usually