Transcript Immunosuppression

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Background (K)
Induction agents (M)
Overview of Immunosuppressants (K)
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Calcineurin inhibitors
Antiproliferative agents
Proliferation signal inhibitors (MTOR inhibitors)
Glucocorticoids
Practical use (M)
› Protocols
› Monitoring
› Side effect management
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Recent trials and “the future” (K)
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History of
Immunosuppression
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1954: First successful renal transplant
› Identical twin donor w/o immunosuppression
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1959: First successful allograft
› Non-identical twin
› Sublethal total body irradiation
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1962: First successful unrelated allograft
› Azathioprine
› >1 yr survival
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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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Cumulative Incidence of Death
Relative Incidence of Death
Taylor, et al. JHLT Oct 2009.
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Immunosuppression Theory
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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
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› 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
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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)
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Major toxicities:
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Renal insufficiency
HTN
Diabetes > Cyclosporin
Dyslipidemia
Hypomagnesemia/Hyperkalemia
Neuro Sx (ie tremors, HA)
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Tacrolimus Drug Interactions
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Inhibit CYP450
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Azoles
Calcium channel blockers
Amiodorone
Mycins
Metronidazole
Grapefruit
Red yeast
Potentiate CYP 450
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Rifampin
Phenytoin
Topiramate
St John’s Wort
echinacea
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Antiproliferative Agents
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Prodrug hydrolyzed into 6Mercaptopurine (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
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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
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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
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Drug interactions
› Rifampin
› Sevelamer
› Daptomycin
› Clindamycin
› Pamidronate
› vancomycin
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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:
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› 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
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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 antiinflammatory 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
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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
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Calcineurin Inhibitor
› Cyclosporine
› Tacrolimus
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Anti-metabolite
› Azathioprine
› Mycophenolate mofetil
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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%)
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Adapted from AST Fellows Conference
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Practical Considerations
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Tacrolimus
› Slow uptitration
› Rapid metabolizers?
› May not need to have level 10-15 for
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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
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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
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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
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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
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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
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Mycophenolate
› Neutropenia
 Adjust dose
› GI effects
 Adjust dose
 Consider changing to AZA
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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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@ 12 months
@ 24 months
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Adverse Events
19% d/c’d therapy
in Sirolimus group
14% d/c’d therapy
in CI group (p NS)
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PSI used instead of CI in 20 heart transplant pts with
significant preop renal dysfunction (mean GFR < 30)
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11 (55%) had
rejection (2
died)
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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 noninferior to conventional dual therapy w/o increase in
rejection, graft vasculopathy or 3 yr mortality
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Early d/c of
steroids was
successful
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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
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