Immunosuppression in
Liver Transplantation
潘思憓 藥學博士
Shi-Hui Pan, ., FCCP
Transplant Pharmacist
Center for Liver Diseases & Transplantation
Cedars-Sinai Medical Center
Los Angeles, California
Objectives
¨Current immunosuppressive drugs
Pharmacotherapy and limitations
¨Principles of immunosuppression
Individualizing
Tapering (who, when, what, and how)
¨ Immunosuppressive strategies
Sparing, withdrawal, or avoidance
Rejection, disease specific
Liver Transplant Team
¨ Surgeons and hepatologists
¨Medical consultants
¨ Psychiatrist and social worker
¨Coordinators, OR, and unit nurses
¨ Pharmacist
¨ Procurement/perfusion specialist
¨ Financial specialist
¨Dietitian
¨Research and administrative teams
Challenges in
Immunosuppression
¨1990 Improve short-term survival
acute rejection
infection
¨2000 Improve long-term survival
chronic rejection
chronic allograft dysfunction
drug induced co-morbidities
Immunosuppressive Agents
¨ 1999 Sirolimus (Rapamune); Thymoglobulin
¨ 1998 Basiliximab (Simulect)
¨ 1997 Daclizumab (Zenapax)
¨ 1995 Mycophenolate (CellCept); Neoral
¨ 1994 Tacrolimus (Prograf, FK 506)
¨ 1986 Muromonab-CD3 (OKT3)
¨ 1983 Cyclosporine (Sandimmune)
¨ 1981 Anti-thymocyte globulin (Atgam)
¨ 1963 Corticosteroid
¨ 1962 Azathioprine
Challenges in Graft Survival
Organ
Transplant
Chronic Graft
Dysfunction
Acute
Rejection
Chronic
Rejection
GRAFT
LOSSshort-term long-term
Immunosuppressive Classes
Induction
¨Polyclonal antibody
Atgam, Thymoglobulin
¨Monoclonal antibody
OKT3
IL-2R antagonists
(Simulect, Zenapax)
Immunosuppressive Classes
Maintenance
¨Calcineurin inhibitor
Neoral, Prograf
¨Antimetabolite
Imuran, CellCept
¨TOR inhibitor
Rapamune
¨Corticosteroid
Immunosuppressive Agents
Pharmacology
¨Azathioprine, Mycophenolate (CellCept)
Anti-metabolite
Inhibits T-cell and B-cell proliferation
by blocking purine synthesis
¨Corticosteroid
Anti-inflammatory effect
Inhibits T-cell and B-cell proliferation
Inhibits phagocytosis
Immunosuppressive Agents
Pharmacology
¨Cyclosporine (Neoral), Tacrolimus (Prograf)
Calcineurin inhibitor
Inhibits T-cell activation by blocking
IL-2 production
¨Sirolimus (Rapamune)
TOR (target of rapamycin) inhibitor
Inhibits TOR enzyme
Blocks IL-2 driven T-cell proliferation
Immunosuppressive Agents
Pharmacology
¨OKT3 (Muromonab-CD3)
Murine mAb blocks T3 receptor
Inhibits T-cell activation
¨Daclizumab (Zenapax), Basilixmab (Simulect)
IL-2R antagonist: mAb blocks IL-2R
Zenapax: humanized Ab
Simulect: chimeric human/mouse Ab
Inhibits proliferation of activated T-cell
Immunosuppressive Agents
Pharmacology
¨Anti-Thymocyte Globulin
Polyclonal Ab
Depletes T-cells
Atgam: immunizing horse
Thymoglobulin: immunizing rabbit
排斥
某些肝病覆發
感染
乙肝, 丙肝覆發
藥物引起副作用
癌症(覆發, 新生)
抗排斥藥的使用
不足過多
Drug Induced Co-Morbidities
¨Nephrotoxicity
¨Hypertension
¨Hyperglycemia
¨Hyperlipidemia
¨Myelosuppression
¨GI complications
¨Malignancy
¨Allergy reaction
¨Serious infection
¨Delay wound healing
¨Bone diseases
¨Neurotoxicity
¨Psychiatric diseases
¨Hepatotoxicity
¨Cosmetic changes
¨Impaired growth
Current Immunosuppression
Limitations
¨Ineffective therapy for chronic rejection
¨Marginal activity in preventing B cell
function but remarkable activity in
suppressing bone marrow
¨Lack of specific immunologic monitoring
¨Significant drug induced co-morbidities
¨Complex drug interactions
¨Expensive
Immunosuppressive Protocols
Principal
¨ Individualizing
High risk patients
¨Optimizing combination regimens
Balance rejection and co-morbidities
¨ Improving long-term survival
¨Tapering immunosuppression over time
¨Enhancing quality of life & compliance
¨Minimizing medication costs
Immunosuppressive Protocols
Individualizing
¨Allograft: size, quality, ischemic time
¨Donor: BMI, viral and hepatitis serology
¨Recipient: age, no of transplant
Co-morbidities
Underlying medical diseases
Underlying liver disease
Drug interactions
¨Donor-recipient compatibility: ABO
Optimize Immunosuppression
Allograft and Donor Factors
¨Preservation injury
¨Steatosis, BMI
¨Full size vs partial size
¨Live donor vs deceased donor
¨Anti-HBc positivity
¨Anti-HCV positivity
¨EBV, CMV serology
Optimize Immunosuppression
Recipient Factors
¨Co-morbidities
Infection, malnutrition, dialysis
¨Underlying medical diseases
DM, CAD, osteoporesis, gastritis
¨Underlying liver disease
AIH, PSC, PBC
HBV, HCV, Hepatoma
Indication for re-transplant
Immunosuppressive Protocols
Combination Regimens
Rationale
¨Combine agents with different
mechanisms and different toxicities
¨Maintain immunosuppression while
reducing co-morbidities with low dose
of each agent
¨Specific for individual
FK + MMF + CS
FK + MMF Neoral + MMF
Neoral + MMF + CS
FK + Rapa +MMF + CS Rapa + MMF + CS
FK + Rapa + CS
Neoral + Rapa
FK + Rapa + MMF Rapa + MMF
FK + CS Neoral + CS
Neoral + Rapa + CS
FK + Rapa
Immunosuppression = A + B + C + ??
Immunosuppressive Protocols
Long-Term Survival
¨Prevent chronic rejection
Reduce episodes of acute rejection
¨Prevent chronic allograft dysfunction
Reduce drug-induced co-morbidities
infection prophylaxis
other concurrent therapy
Prevent recurrent disease
Reduce delayed graft function
Tapering Immunosuppression
¨Review of literature
Clinical trials to clinical practice?
¨Who is a candidate?
Low risk for rejection
High risk for co-morbidities
¨When to safely taper?
¨What strategy to use?
¨How to implement?
Tapering Immunosuppression
Who
¨Good candidates
Low risk for rejection
High risk for co-morbidities
PTDM, PTLD, DGF, infection,
recurrent diseases, CV or bone
diseases, renal dysfunction, anemia
Poor quality of life or compliance
¨Poor candidates: autoimmune disorders
Tapering Immunosuppression
When
¨Time of post-transplant
De novo patients
Stable patients
Short-term vs long-term
Co-morbidities driven
Recurrent disease driven
Tapering Immunosuppression
What
¨Current strategies
sparing, withdrawal, avoidance
¨Maintenance regimens
triple, double, mono
¨Determine the individual’s net state of
immunosuppression
¨Ultimate goal is to maintain good graft
function and improve quality of life
Tapering Immunosuppression
How
¨How fast to reduce immunosuppression
Avoidance: not to use
Withdrawal: stop or rapid taper
¨How much to reduce immunosuppression
Sparing: degree of minimization
¨Rejection episode is affected by:
Timing, speed, and degree of tapering
¨Key is to closely monitor the response
Review of Literature (I)
Evaluation of Clinical Trials
¨Study design and sample size
¨Graft characteristics
¨Patient characteristics & medical diseases
¨Donor characteristics
¨Donor/patient compatibility
¨ Inclusion/exclusion criteria
¨Treatment comparisons
¨Endpoints and conclusion
Review of Literature (II)
Interpretation of Literature
¨Power
¨Significance (statistical vs clinical)
¨Causes and incidences of withdrawal
¨Drug formulation, dose, or level
¨Study population
¨Study bias (confounding effect)
¨Study limitations (ethic)
¨Reproducible (study validity)
Immunosuppressive Protocols
Medication Costs
¨Induction: $2000-5000/course
¨Maintenance : $1100-1300/month
¨Concurrent drug costs
¨Cost of drug monitoring
¨Infusion related costs
¨Cost of hospitalization due to drug
associated co-morbidities
Medication Costs 2002 (AWP)
¨OKT3 5mg x 7
$ 5040
¨Thymo 100mg x 7
$ 5404
¨Simulect 20mg x 2
$ 2018
¨Zenapax 75mg x 5
$ 5173
¨Neoral 425mg x 30
$ 757
¨Prograf x 30
$ 701
¨Cellcept 2gm x 30
$ 547
¨Rapamune 2mg x 30
$ 411
換肝的費用
ＭediCare, MediCal 及私人保險公司給付
不准抽煙, 喝酒, 使用非法藥物
MediCare 只付抗排斥藥
抗排斥藥每月約 $1100 - 1300
每月注射 B 型肝炎球蛋白約 $600-700
Epivir 每月約 $150, Hepsera 每月約 $600
其它藥物費用
Immunosuppression
Current Strategies
To maintain the current
low level of acute rejection
and improve long-term
graft function with
reduced patient risk.
Immunosuppressive Strategies
Induction (I)
¨Rationale
Prevent ACR in high risk patients
Delay CNI administration in
patients with renal impairment
¨ Increased risk of infection, PTLD, and
recurrent diseases (HBV, HCV)
¨Unlike kidney transplant, the role of IL
-2R antagonists not clear
Immunosuppressive Strategies
Induction (II)
¨Not widely used in liver transplantation
Transplant sicker patients
T-tube drainage less common
New potent agent available: Prograf
New formulations available
Neoral: non bile-dependent
CellCept: IV preparation
肝臟移植之簡介
Model for End-Stage Liver
Disease (MELD)
¨National system started in 3/2002
¨MELD risk score =
10 x [ x loge (Creatinine mg/dL)
+ x loge (Bilirubin mg/dL)
+ x loge (INR)]
¨All patients assigned a score (6-40)
Application of MELD
¨Priorities
hepatoma (MELD = 24)
hepatorenal syndrome
cholestatsis
coagulopathy
¨Los Angeles: > 30-40 points
Cr. , Bili , INR ()
Calculated MELD = 40
¨Regional review board
IL-2R Antagonists
Pharmacotherapy
¨Not justified for cost-effectiveness
modest reduction in ACR
has to use with CNI
expensive
not indicated for treatment of ACR
¨Post marketing Anaphylaxis warning
initial and/or re- exposures
Immunosuppressive strategies
Calcineurin Inhibitor (I)
¨Sparing, withdrawal, avoidance
improve nephropathy, neurotoxicity,
diabetic, hypertension, cosmetic
MMF- or TOR inh- based regimen
results varied
¨Comparisons of CSA and FK
results varied
Immunosuppressive strategies
Calcineurin Inhibitor (II)
¨Chronic rejection
? interferon
¨Refractory ACR
¨Osteoporosis
¨AIH, PSC, PBC
¨Hyperlipidemia
¨Monotherapy
¨Hirsutism
¨Neurotoxicities
¨High risk for
EBV infection
¨High risk for DM
¨? PBC
¨Alopecia
Roles of FK Roles of CSA
Calcineurin Inhibitor
Pharmacotherapy
¨ IV preparation not routinely used
¨Prograf is more potent than Neoral
¨Higher level/dose ratio reported in LDLT
¨No difference in recurrence of HCV
¨Effective lower levels demonstrated
as mono- or combined therapy
HBV, HCV
reduce toxicities
Immunosuppressive strategies
Mycophenolate
¨Sparing, withdrawal, avoidance
reduce myelosuppression, GI disorders
optimize CMV or hepatitis C therapy
¨Synergistic anti-CMV effect with ganciclovir
¨Anti-HCV effect controversial
¨Role in combination regimens
induction therapy with IV preparation
CNI or steroid sparing agent
autoimmune hepatitis
refractory or chronic rejection
Mycophenolate
Pharmacotherapy
¨Therapeutic drug monitoring not clear
MMF trough level or MPA AUC
IMPDH activity
¨One size doesn’t fit all
high protein bound drug
dose limiting side-effects
dose adjustment in renal impairment
Mycophenolate
Mofetil (MMF)
Mycophenolic
Acid (MPA)
Mycophenolic
Acid Glucoride
(MPAG)
hydrolysis
conjugation
Mycophenolate Pathway
Immunosuppressive strategies
Corticosteroid
¨Sparing, withdrawal, avoidance
improve severe infection, diabetic, CV or
bone diseases, wound healing, growth
impairment, hyperlipidemia, adrenal insuff.
clear-cut benefit not demonstrated
prevent recurrent diseases
HBV, ? HCV, HCC
increased long-term graft failure noted
AIH, PSC, PBC
Corticosteroid
Pharmacotherapy
¨Markedly inhibit cell cycle progression
may interfere liver regeneration
¨Recurrent HCV (incidence/severity)
pulse dose, longer exposure: viremia
faster taper: partial immune restoration
¨Avoidance
what incidence of ACR acceptable?
impact on chronic rejection
Immunosuppressive strategies
Sirolimus
¨Role in liver transplant not clear
warning: HAT, mortality, graft loss
other limitations: wound infection,
hyperlipidemia, myelosuppression
therapeutic ranges not established
role as primary or adjunct not clear
¨Special considerations
CNI and/or CellCept intolerance
refractory ACR or chronic rejection
anticancer, antifibrotic (TGF-ß) effects
Sirolimus
Pharmacotherapy
¨Lack of neurotoxicity, nephrotoxicity,
diabetogenesis
¨Antiproliferative actions may interfere
hepatocyte regeneration
¨Long half-life (efficacy vs toxicities)
¨Many drug interactions
Neoral: time of administration
Prograf
¨Drug monitoring not widely available
¨Hyperlipidemia not easily managed
Immunosuppressive strategies
MELD Era
FK + MMF + CS
CSA + CS
CSA + CS FK
FK + CS
FK + MMF
FK + MMF + CS
neurotoxicity nephrotoxicity
Immunosuppressive strategies
LDLT
¨May incidence and severity of ACR
¨Higher CNI level/dose ratio noted
lower initial doses recommended
reduced hepatic clearance due to
incomplete regeneration and
reduced hepatic metabolism
Immunosuppressive strategies
HBV, HCV, HCC
¨Avoid induction
¨Minimize global immunosuppression
lower CNI levels
avoid antimetabolite if possible
steroid minimization or withdrawal
¨Avoid empirical treatment of ACR
¨Minimize steroid pulse in treatment of ACR
Immunosuppressive strategies
Liver and Kidney Tx
¨ Immunologic advantage
only seen from same donor
immunosuppression depends on LT
antibody induction rarely needed
MMF induction for CNI sparing
long term low dose steroid controversial
¨Kidney rejection uncommon
Immunosuppressive strategies
Renal Impairment
¨Optimize immunosuppression
balance risk of infection vs rejection
antibody induction rarely needed
immediately post-op:
MMF induction and delay CNI
long term:
MMF maintenance and reduce CNI
diabetes: withdraw steroid & reduce CNI
¨Dialysis prone to infection than rejection
Immunosuppressive strategies
Acute Cellular Rejection
¨R/O viral infection or hepatobiliary
complications before treatment
¨Steroid pulse + taper
monitor BP and blood sugar
¨Optimize CNI levels
switch Neoral to Prograf
¨Add MMF or optimize dose
¨OKT3 or ATG rarely needed
Immunosuppressive strategies
Chronic Rejection
¨Switch Neoral to Prograf
¨Add MMF or optimize dose
¨Add Rapamune
¨Often associated with non-compliance
¨OKT3 or ATG not effective
¨Re-transplant rarely needed
FK 506 for Chronic Rejection
1 Yr Graft & Patient Survival
N Graft % Patient %
All Patients 91 70 84
< 3M post-LT 15 52 66
> 3M post-LT 76 73 88
. <10mg/dl 52 86 95
. >10mg/dl 39 52 71
Case Study
37 years old female with ARF (on continuous
renal replacement therapy) underwent LT
for FHF due to Tylenol overdose
HD Cr. ALT WBC Plt FK MMF CS
D1 Y 4060 82 < 1g/d 200
D4 Y 1254 28 1g/d 80
D10 Y 141 86 20
D21 Y 20 2g/d 20
M1 N 15 2g/d
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