The Calcineurin Inhibitor Tacrolimus Reduces Proteinuria in ...
1. 2 Background (K) Induction agents (M) Overview of Immunosuppressants (K) › Calcineurin...
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Transcript of 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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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
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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