1. 2 background (k) induction agents (m) overview of immunosuppressants (k) › calcineurin...

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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)

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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

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Heart Transplant Survival

Taylor, et al. JHLT Oct 2009.

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Relative Incidence of Death

Cumulative Incidence of Death

Taylor, et al. JHLT Oct 2009.

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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

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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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Induction Therapy

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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

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Induction Therapy

ATGAM (Equine) Thymoglobulin (Rabbit) OKT3 Dacluzimab Basiliximab Alemtuzumab

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Immunosuppression Agents

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Calcineurin Inhibitors

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Halloran NEJM 2005; 351 (26):2715

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Peptide derived from fungus Tolypocladium inflatum

Older CI introduced 1983 Multiple formulations

› Oil-based (variable absorption)› Microemulsion (preferred)

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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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Previously called FK-506 Macrolide derived from fungus

Streptomyces tsukabaensis Approved for heart transplant in 2006 *Currently most widely used CI

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Dosing: › PO: q 12 hr dosing at 0.05-0.1 mg/kg/day to

acheive trough 10-15 ng/mL (<6 mos) and 5-10 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)

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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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Antiproliferative Agents

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

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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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Prodrug hydrolyzed into mycophenolic acid (active form) More recent agent that is now

preferred to azathioprine

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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)

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Mycophenolate Mofetil

Drug interactions› Rifampin› Sevelamer› Daptomycin› Clindamycin› Pamidronate› vancomycin

Category X

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Proliferation Signal Inhibitors (MTOR Inhibitors)

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

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Corticosteroids

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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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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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Practical Use of Immunosuppression

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Standard Immunosuppressive Regimen

Calcineurin Inhibitor› Cyclosporine› Tacrolimus

Anti-metabolite› Azathioprine› Mycophenolate mofetil

Steroids

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Standard Regimens

Taylor, et al. JHLT Oct 2009.

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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

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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

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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

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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

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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

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VCU Protocol

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VCU Protocol

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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

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Managing Side Effects

Mycophenolate› Neutropenia

Adjust dose› GI effects

Adjust dose Consider changing to AZA

Steroids› wean ASAP

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The Future of Immunosuppression for Heart Transplant

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

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

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Freedom from rejection 2R/3R

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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

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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

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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