1. 1

2. 2  Background (K)  Induction agents (M)  Overview of Immunosuppressants (K) › Calcineurin inhibitors › Antiproliferative agents › Proliferation signal inhibitors (MTOR inhibitors) › Glucocorticoids  Practical use (M) › Protocols › Monitoring › Side effect management  Recent trials and “the future” (K)

3. 3 History of Immunosuppression  1954: First successful renal transplant › Identical twin donor w/o immunosuppression  1959: First successful allograft › Non-identical twin › Sublethal total body irradiation  1962: First successful unrelated allograft › Azathioprine › >1 yr survival  1963: Reversal of rejection with steroids  1967: First Heart Transplant—died of rejection in several days Adapted from AST Fellows Conference

4. 4 Heart Transplant Survival Taylor, et al. JHLT Oct 2009.

5. 5 Relative Incidence of Death Cumulative Incidence of Death Taylor, et al. JHLT Oct 2009.

6. 6 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

7. 7 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

8. 8 Induction Therapy

9. 9  Provide the most intense therapy when alloimmune response is greatest  “Induce” tolerance  Provide background immunosuppression during immediate post op period while renal function stabilizes

10. 10 Induction Therapy  ATGAM (Equine)  Thymoglobulin (Rabbit)  OKT3  Dacluzimab  Basiliximab  Alemtuzumab

11. 11 Immunosuppression Agents

12. 12 Calcineurin Inhibitors

13. 13 Halloran NEJM 2005; 351 (26):2715

14. 14  Peptide derived from fungus Tolypocladium inflatum  Older CI introduced 1983  Multiple formulations › Oil-based (variable absorption) › Microemulsion (preferred)

15. 15  Dosing: › PO: q 12 hrs at 4-8 mg/kg/day to achieve trough levels 250-350 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

16. 16  Previously called FK-506  Macrolide derived from fungus Streptomyces tsukabaensis  Approved for heart transplant in 2006  *Currently most widely used CI

17. 17  Dosing: › PO: q 12 hr dosing at 0.05-0.1 mg/kg/day to acheive trough 10-15 ng/mL ( 6 mo) › IV: continuous infusion – 1/3 of daily oral dose (difficult to regulate)  Major toxicities: › Renal insufficiency › HTN › Diabetes > Cyclosporin › Dyslipidemia › Hypomagnesemia/Hyperkalemia › Neuro Sx (ie tremors, HA)

18. 18 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

19. 19 Antiproliferative Agents

20. 20

21. 21  Prodrug hydrolyzed into 6- Mercaptopurine (active form)  Older antiproliferative agent not widely used

22. 22  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

23. 23  Prodrug hydrolyzed into mycophenolic acid (active form)  More recent agent that is now preferred to azathioprine

24. 24  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)

25. 25 Mycophenolate Mofetil  Drug interactions › Rifampin › Sevelamer › Daptomycin › Clindamycin › Pamidronate › vancomycin  Category X

26. 26 Proliferation Signal Inhibitors (MTOR Inhibitors)

27. 27

28. 28  Macrolide derived from fungus Streptomyces hygroscopicus  Structurally similar with FK binding (like tacrolimus) independent of calcineurin mechanism  Current uses: › renal insufficiency › CAV › Malignancy

29. 29  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

30. 30  Analog of Sirolimus  Recent approval for renal transplant  Being investigated for heart transplant

31. 31 Corticosteroids

32. 32

33. 33  Nonspecific anti- inflammatory that interupts multiple steps in immune activation  Highly effective for prevention of rejection  Many adverse-effects long-term

34. 34  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

35. 35 Practical Use of Immunosuppression

36. 36 Standard Immunosuppressive Regimen  Calcineurin Inhibitor › Cyclosporine › Tacrolimus  Anti-metabolite › Azathioprine › Mycophenolate mofetil  Steroids

37. 37 Standard Regimens Taylor, et al. JHLT Oct 2009.

38. 38 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

39. 39 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

40. 40 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

41. 41 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

42. 42 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

43. 43 VCU Protocol

44. 44 VCU Protocol

45. 45 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

46. 46 Managing Side Effects  Mycophenolate › Neutropenia  Adjust dose › GI effects  Adjust dose  Consider changing to AZA  Steroids › wean ASAP

47. 47 The Future of Immunosuppression for Heart Transplant

48. 48

49. 49  Comparison of MMF + Sirolimus to MMF + CI for preservation of renal function in renal transplants

50. 50 Adverse Events  19% d/c’d therapy in Sirolimus group  14% d/c’d therapy in CI group (p NS) @ 12 months @ 24 months

51. 51

52. 52  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

53. 53

54. 54  Steroids used in early post-op period but w/drawn by post-op week 8-9

55. 55 Freedom from rejection 2R/3R

56. 56  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

57. 57 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

58. 58 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