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Immunosuppression Theory:

1 Immunosuppression Theory Having a heart transplant is “trading one set of problems for another” Multi-drug therapy--Why? Any 1 agent, if used at high doses, could prevent rejection Too toxic and intolerable! Multidrug regimens allow for lower doses of each, minimizing toxicity, while providing adequate immunosuppression Work at different signals of immune activation

Goals of Immunosuppression:

2 Goals of Immunosuppression Challenges for post-transplant recipients… To provide adequate immunosuppression Minimize adverse effects Treat adverse effects and chronic, drug-related problems Screening for drug-related complications Our drugs are good for preventing acute rejections but not chronic, Ab mediated rejection Recent improvement in short-term outcomes Less improvement in long-term outcomes No recent, promising agents so focus is on different combinations, reduced dosing to improve outcomes

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3 Induction Therapy

Induction Therapy:

4 Induction Therapy Provide the most intense therapy when alloimmune response is greatest “Induce” tolerance Provide background immunosuppression during immediate post op period while renal function stabilizes

Induction Therapy:

5 Induction Therapy ATGAM (Equine) Thymoglobulin (Rabbit) OKT3 Dacluzimab Basiliximab Alemtuzumab

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6 Immunosuppression Agents

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7 Calcineurin Inhibitors

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8 Halloran NEJM 2005; 351 (26):2715

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9 Peptide derived from fungus Tolypocladium inflatum Older CI introduced 1983 Multiple formulations Oil-based (variable absorption) Microemulsion (preferred)

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10 Dosing: PO: q 12 hrs at 4-8 mg/kg/day to achieve trough levels 250-350 ng/mL (< 6 mo), 200-250 ng/mL (6-12 mo), 100-200 ng/mL (> 1yr) IV: q 12 hr infusions or continuous IV infusion at 1/3 daily oral dose Major Toxicities: Renal insufficiency HTN > Tacrolimus Dyslipidemia > Tacrolimus Hypokalemia/hypomagnesemia Hyperuricemia Neurotoxicity ( encephalopathy, seizures , tremors, neuropathy ) Gingival hyperplasia Hirsutism

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11 Previously called FK-506 Macrolide derived from fungus Streptomyces tsukabaensis Approved for heart transplant in 2006 *Currently most widely used CI

Tacrolimus Drug Interactions:

12 Tacrolimus Drug Interactions Inhibit CYP450 Azoles Calcium channel blockers Amiodorone Mycins Metronidazole Grapefruit Red yeast Potentiate CYP 450 Rifampin Phenytoin Topiramate St John’s Wort echinacea

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13 Dosing: PO: 1.5-3.0 mg/kg/day (keep WBC > 3,000) IV: same as po Levels not monitored Major Toxicities: Bone marrow suppression Hepatitis Pancreatitis Malignancy

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14 Prodrug hydrolyzed into mycophenolic acid (active form) More recent agent that is now preferred to azathioprine

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15 Dosing: PO: tab or capsule at 500 mg-1500 mg bid IV: 2 hr infusion q 12 hrs at same dose po Levels not generally followed Major Toxicities: GI (nausea, gastritis, diarrhea) Enteric coated mycophenolate Na may be better tolerated Leukopenia and thrombocytopenia (dose-related)

Mycophenolate Mofetil:

16 Mycophenolate Mofetil Drug interactions Rifampin Sevelamer Daptomycin Clindamycin Pamidronate vancomycin Category X

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17 Proliferation Signal Inhibitors (MTOR Inhibitors)

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18

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19 Macrolide derived from fungus Streptomyces hygroscopicus Structurally similar with FK binding (like tacrolimus) independent of calcineurin mechanism Current uses: renal insufficiency CAV Malignancy

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20 Dosing: PO: available as liquid or tablet;1-3 mg daily with goal trough of 5-10 ng/mL (assays vary) Interacts with cyclosporine; must be dosed > 4 hrs apart Major toxicities: Oral ulcers Dyslipidemia Poor wound healing Edema Pneumonitis, alveolar hemorrhage Bone marrow suppression (anemia and thrombocytopenia) Potentiates CI nephrotoxicity

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21 Analog of Sirolimus Recent approval for renal transplant Being investigated for heart transplant

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22 Corticosteroids

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23

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24 Nonspecific anti- inflammatory that interupts multiple steps in immune activation Highly effective for prevention of rejection Many adverse-effects long-term

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25 Dosing: PO: 1 mg/kg/day divided into bid dosing early with rapid tapering to < 0.05 mg/kg/day by 6-12 mo IV: Methylprednisolone with similar dosing Major toxicities: Weight gain, HTN, HLD, Osteopenia, Hyperglycemia, poor wound healing, Salt/H2O retention, myopathy, cataracts, PUD

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26 Practical Use of Immunosuppression

Standard Immunosuppressive Regimen:

27 Standard Immunosuppressive Regimen Calcineurin Inhibitor Cyclosporine Tacrolimus Anti-metabolite Azathioprine Mycophenolate mofetil Steroids

Standard Regimens:

28 Standard Regimens Taylor, et al. JHLT Oct 2009.

Standard Regimens:

29 Standard Regimens Tac/Steroid/MMF or MPA (49%) Cyclosporin/Steroid/MMF or MPA (28.5%) Tac/MMF or MPA (3.8%) Tac/Steroid (1.9%) Steroid/MMF or MPA (0.9%) Tac alone (0.6%) Adapted from AST Fellows Conference

Practical Considerations:

30 Practical Considerations Tacrolimus Slow uptitration Rapid metabolizers? May not need to have level 10-15 for immunosuppressive effect Draw as trough level If level supertherapeutic, ask pt if he took drug before level drawn—don’t assume either way Use 1 mg capsules IV formulation difficult to titrate Generic ok

Practical Considerations:

31 Practical Considerations Mycophenolate Can take with food/meds GI symptoms responsive to change in dose Switch to AZA if not tolerated Suspend/change dose for WBC<3.5 Generic ok

Practical Considerations:

32 Practical Considerations Steroids Wean as quickly as condition allows Divide dose when > 20mg daily Infection prophylaxis when >10mg daily Give with food Not all weight gain is steroid-induced Encourage weight bearing exercise for bone health

Practical Considerations:

33 Practical Considerations Drug Monitoring Tacrolimus TROUGH level 10-15ng/dl 3 doses before respond to level Mycophenolate questionable utility Sirolimus Trough level Takes several doses for level to stabilize

VCU Protocol:

34 VCU Protocol

VCU Protocol:

35 VCU Protocol

Managing Side Effects:

36 Managing Side Effects Tacrolimus Tremor Toxicity? Adjust dose Clonazepam HTN Higher in morning Anti-hypertensives CCB will potentiate level Nephrotoxicity Adjust dose Consider alternative agent Hyperlipidemia Treat appropriately

Managing Side Effects:

37 Managing Side Effects Mycophenolate Neutropenia Adjust dose GI effects Adjust dose Consider changing to AZA Steroids wean ASAP

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38 The Future of Immunosuppression for Heart Transplant

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39

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40 Comparison of MMF + Sirolimus to MMF + CI for preservation of renal function in renal transplants

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41 Adverse Events 19% d/c’d therapy in Sirolimus group 14% d/c’d therapy in CI group (p NS) @ 12 months @ 24 months

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42

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43 PSI used instead of CI in 20 heart transplant pts with significant preop renal dysfunction (mean GFR < 30) 11 (55%) had rejection (2 died) ½ converted to CI due to PSI adverse effects

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44

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45 Steroids used in early post-op period but w/drawn by post-op week 8-9

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46 Freedom from rejection 2R/3R

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47 Immunosuppression with Tacrolimus only was non-inferior to conventional dual therapy w/o increase in rejection, graft vasculopathy or 3 yr mortality Early d/c of steroids was successful Limited power due to small sample size

Summary:

48 Summary Immunosuppression regimens have improved greatly since beginning of transplantation 3 drug regimens with tapering of steroids are standard of care Current challenges are providing adequate immunosuppression and minimizing complications of drugs

Summary:

49 Summary Current efforts are focused on further minimization of immunosuppression and use of alternative regimens While much of transplant and immunosuppression are protocol driven, regimens should be individualized! Predicting those who are more likely to have rejection can be difficult

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