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“Oh great! We have a transplant
patient on our service”
Transplant for the Non-Transplant
Clinician
Nicole A. Weimert, PharmD, BCPS
Clinical Specialist, Solid Organ Transplantation
Assistant Clinical Professor, USC-COP
Medical University of South Carolina
Department of Pharmacy Services
Objectives




Provide a brief review of transplant immunology and
immunosuppression
Review common drug, disease, immunosuppression
interactions
Describe situations and solutions related to
administration of immunosuppressants
Discuss common case-based scenarios related to
the presentation of transplant recipients with nontransplant related issues
Immunology 101
Maintaining the Balance
Infection
Malignancy
Graft Function
Life Saving
Procedure
Transplanted Organ
= Antigen


“Antigen” – any substance that causes the
production of an immune response
The transplanted organ is non-self and its cell
surface protiens are functional antigens
Cells of the Immune System
Antigen
Presenting
Cell
T cell
B cell
Y
9 steps……
APC
= Antigen
1.
2.
The antigen presenting cell (APC) envelops
circulating antigen
The antigen is processed within the APC into small
protein fragments called peptides
HLA
3.
4.
APC
The peptides bind to human leukocyte antigen
(HLA)
The HLA/peptide complex migrate to the cell
membrane of the APC
APC
5.
The APC presents the
HLA/peptide complex to
T cells
6.
T cell receptors (TCR)
on T cells recognize a
specific HLA/peptide
7.
T cell activate and
initiate proliferation via a
complex pathway
TCR
CD3
T cell
cytokines
APC
IL-2 R
HLA
IL-2
Calcineurin
TCR
A
NF-AT
DNA
synthesis
IL-2 gene
T Cell
B cell activation
Y
cytokines
T cell
8.
9.
B cell
Plasma
cell
Cytokines activate and induce proliferation of B
cells
B cells produce antibodies specific to the antigen
Rejection
T cell
B cell
Y


Y
T cells directly attack the transplanted organ
Antibodies produced by B cells lead to the
destruction to the transplanted organ
The Immune System





Specificity : distinguish between non-cross reacting
antigens.
Memory: quick and vigorous response to a
subsequent but similar pathogen or antigen
Mobility: local reactions to provide systemic
protection.
Replication: amplifies the immune response.
Redundancy: produce components with the same
biological effect but produced from multiple cell lines
Common Issues
Review of Drug Disease State
Interactions
Question:
This transplant patient was
admitted for urosepsis. What
should we do with their
immuosuppression?
Infection and Transplant

Facts:

Inefficient immune systems



Be aggressive with initial treatment
Consider the consequences of organ dysfunction
if immunosuppression is held
How far out from transplant
Infection and Transplant

Facts:


Inefficient immune systems
Consider the consequences of organ dysfunction
if immunosuppression is held


Heart versus Kidney
How far out from transplant
Infection and Transplant

Facts:



Inefficient immune systems
Consider the consequences of organ dysfunction
if immunosuppression is held
How far out from transplant

Risk of acute rejection decreases further out from
transplant


Have they had a recent rejection episode
Are they compliant
What should we stop first?
Pick the agent that has the broadest
spectrum of activity:

A.
B.
C.
D.
Corticosteroids
Mycophenolic Acid
Tacrolimus
Cyclosporine
What should we stop first?
Pick the agent that has the broadest
spectrum of activity:

A.
B.
C.
D.
Corticosteroids
Mycophenolic Acid
Tacrolimus
Cyclosporine
Why can’t we just stop
the corticosteroids?
Adrenal Axis Suppresion
Exposure to
corticosteroids


for < 3 weeks rarely
induces clinical adrenal
suppression
Kronenberg: Williams Textbook of Endocrinology, 11th ed.
Question: Supplementation

Do transplant recipients on chronic steroids
need supplemental doses during periods of
acute stress (surgery, infection)?

YES or NO
Question: Supplementation


Do transplant recipients on chronic steroids
need supplemental doses during periods of
acute stress (surgery, infection)?
DEPENDS
Concerns:


Impaired wound healing
Further immunosuppression
Transplantation. 1991;51:385-390
Historical Evidence

Bromberg et al.

Prospective evaluation of kidney transplant
recipients admitted with physiological stress


Surgery, sepsis, metabolic abnormalities
N=40



Did not receive supplemental steroid doses
Remained on admission dose (5 to 10 mg/day)
Measurements
 Serum cortisol levels elevated in 56%
 Urine cortisol levels elevated in 79%
 Cosyntropin stimulation tests overestimated adrenal
suppression in 63%
Transplantation. 1991;51:385-390
J Am Coll Surg. 1995;180:532-536
Current Evidence

Corticosteroids in Septic Shock: Meta-Analysis
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15 trials (n = 2022)
No recommendations for which populations would benefit
Corticosteroid Therapy of Septic Shock
(CORTICUS)



Efficacy and safety of low-dose hydrocortisone therapy in
septic shock
Multi-center, double blind, randomized, placebo controlled
 Inclusion criteria: adult, sepsis within 72 hrs
 Exclusion criteria: chronic immunosuppression or steroid
use
No change in 28 day mortality
N Engl J Med. 2008;358:111-124
BMJ 2004;329:480-480
Recommendations: Infected
Transplant Recipients



Assess the severity of illness and relative risk
for acute rejection
Discontinue adjunctive agent and minimize
other immunosuppression
Supplement corticosteroids in the setting of
pressor resistant progressive septic shock
Question:
We performed bowel surgery on
this transplant patient, how do
we convert their
immunosuppression to IV?
Question
What is the PO to IV conversion for
calcineurin inhibitors?

A.
B.
C.
D.
1:1
2:1
3:1
4:1
Question
What is the PO to IV conversion for
calcineurin inhibitors?

A.
B.
C.
D.
1:1
2:1
3:1
4:1
Conversion Considerations

Simple answer:

3:1
Tacrolimus.package insert.Astellas.Revised April 2006
Int J Clin Pharmacol Ther. 2004;42:701-718
Conversion Considerations

Simple answer:


3:1
Why this does not work:

Bioavailability:

Tacrolimus : <30%


Trough concentrations have good correlation with ACU
(r2=0.93)
Cyclosporine : erratic, formulation dependent
Tacrolimus.package insert.Astellas.Revised April 2006
Int J Clin Pharmacol Ther. 2004;42:701-718
Conversion Considerations

Simple answer:


3:1
Why this does not work:

Bioavailability:

Tacrolimus : <30%



Trough concentrations have good correlation with ACU
(r2=0.93)
Cyclosporine : erratic, formulation dependent
Race differences:

Oral bioavailability in African-Americans is 20 and 50%
lower than in Caucasians
Tacrolimus.package insert.Astellas.Revised April 2006
Int J Clin Pharmacol Ther. 2004;42:701-718
Conversion Considerations

Infusion

Continuous versus intermittent q 12 hours



Tubing


Hypertension
Renal insufficiency
Must use non-PVC tubing
Drawing levels - will contaminate tubing

Central lines, port-a-cath
Am J Health System Pharm.2008;65:226-228
Recommendations: Converting
Calcineurin Inhibitors to IV



Use a designated line
When in doubt start low
Empiric weight based dosing



Tacrolimus 0.01 – 0.03 mg/kg/day
Cyclosporine 3 – 5 mg/kg/day
Use conversion

“Soft” maximum doses for initiation


Tacrolimus >4 mg in 24 hours
Cyclosporine > 50 mg in 24 hours
Question:
So we have this transplant
patient on cyclosporine.
What level should this
patient be at?
Appropriate Level

Several variables:







Center
Patient
Organ
Time since transplant
Rejection history
Current clinical situation
Concurrent immunosuppression
Appropriate Level

Several variables:



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


Center
Patient
Contact the patient’s
transplant coordinator
Organ
Time since transplant
Rejection history
Current clinical situation
Concurrent immunosuppression
Question:
So we have this transplant
patient on cyclosporine.
How often should we be
getting levels?
Measuring Levels



Compliance
Impending drug interactions
Efficacy


Toxicity


Elevated levels may induce renal artery vasoconstriction
Liver insufficiency


Measure of allograft function
Increased levels
Diarrhea

Increased levels
Pediatr Transplant. 2005;9:315-323
Am J Transplant. 2005;5:1383-1391
Question:
We have to start an azole
antifungal agent. How should
we adjust their medicines
and when will we see the
effect?
Question
What is the primary mechanism of
fluconazole associated with elevations in
the calcineurin inhibitor level?

A.
B.
C.
D.
Liver CYP450 inhibition
Intestinal P-glycoprotein inhibition
Protein binding
Intestinal CYP450 inhibition
Question
What is the primary mechanism of
fluconazole associated with elevations in
the calcineurin inhibitor level?

A.
B.
C.
D.
Liver CYP450 inhibition
Intestinal P-glycoprotein inhibition
Protein binding
Intestinal CYP450 inhibition
Azole Antifungal


Variable and requires frequent monitoring
Cyclosporine:

Romero et al.



Double-blind, placebo controlled cross over, oral
voriconazole
Stable renal transplant recipients (n=53)
2.48 fold increase in CsA trough levels
Clin Pharmacol Ther. 2002;71:226-234
Azole Antifungal and
Calcineurin Inhibitor

If patient has had stable levels


Onset of interaction



Reduce dose in half
24 to 72 hours
Prolonged
Magnitude of interaction for inhibitor

Increased with oral administration
Immunosuppressant
Interacting Drugs
Mechanism
Consequence
Clinical Management
calcinuerin inhibitors
(cyclosporine
and tacrolimus)
and sirolimus
clarithromycin*, erythromycin*,
ketoconazole*, itraconazole*,
fluconazole, voriconazole*,
fluoxetine, fluvoxamine,
citalopram, nefazadone*,
diltiazem*, verapamil*,
delaviridine*, ritonavir*,
cimetidine*, grapefruit juice*,
amiodarone, saquinavir,
nelfinavir, indinavir, amprenavir,
chloramphenicol*
Inhibit CYP450
3A4
isoenzyme
in the liver
and
intestines
Increase the
concentra
tion and
total AUC
of the IS
Either prospectively
decrease the IS dose or
monitor trough
concentrations more
closely and adjust
doses accordingly
calcinuerin inhibitors
(cyclosporine
and tacrolimus)
and sirolimus
carbamazepine*, dexamethasone,
phenobarbital*, phenytoin*, St.
John’s Wort*, rifampin*,
rifabutin*, efavirenz*,
nevirapine*, nafcillin,
clindamycin
Induce CYP450
3A4
isoenzyme
in the liver
and
intestines
Decrease the
concentra
tion and
total AUC
of the IS
Either prospectively
increase the IS dose or
monitor trough
concentrations more
closely and adjust
doses accordingly
calcinuerin inhibitors
(cyclosporine
and tacrolimus),
sirolimus, and
mycophenolate
mofetil
cholestyramine, colestipol, probucol,
sevelamer, antacids
(magnesium and aluminum
containing)**, iron containing
products**
Bind to IS and
prevents
absorption
Decrease the
concentra
tion and
total AUC
of the IS
Avoid concomitant
administration with IS
and monitor trough
concentrations
azathioprine
allopurinol
Inhibits
metabolism
by inhibiting
xanthine
oxidase
Increases the
concentra
tion and
total AUC
of
azathiopri
ne
Avoid use together or
prospectively reduce
azathioprine dose to
1/3 or 1/4 normal dose
and monitor for
increased toxicity
* Indicates potent inhibitor or inducer
** Only occurs with mycophenolate mofetil
Question:
Can we cath a patient with a
kidney transplant who had
marginal renal function?
Cardiovascular Disease and
Renal Transplant Recipients

Annual risk of death from a cardiovascular
related event


3.5% to 5%
50 fold higher than the general population
Transplantation 2006;15:603-611
J Am Soc Nephrol 1998; 9:S16
Contrast Induced Nephropathy

Definition:


Occurs within 24 to 48 hours following
exposure


Absolute (Scr≥0.5 mg/dL) or relative (≥25%)
increase in after exposure to contrast
Peak 3 to 5 days with a return to baseline
Etiology

Direct toxicity to renal tubular epithelium, oxidative
stress, and ischemic injury
Catheterization and Cardiovascular interventions.2008;71:62-72
Clinical Pearls




Do not withhold life-saving treatment
Reversible damage from contrast
Can be attenuated with adequate hydration
Other pharmacological interventions may
decrease the length and severity of injury



Hydration
N-acetylcysteine
Sodium bicarbonate
Pre-Treatment for All
Transplant Recipients
http://www.musc.edu/medcenter/policy/transplant/source/kidney/
Question:
What about the generic
immunosuppressants?
Generic Timeline
Product
Patent
Expired
Generic
Approved
Generic Use in
Transplant
Imuran®
(Azathioprine)
1979
1996
No difference in
outcomes
Neoral®
(Cyclosporine)
1995
1995
Increased rejection
rates
Prograf®
(Tacrolimus)
April 2008
Pending
NDAs
Unknown
Cellcept®
(mycophenolate
mofetil)
May 2009
Pending
NDAs
Unknown
The Ongoing Discussion in
Transplant Circles

Controversy over the current FDA approval
process for generic medication



Bioequivalence study – 18 – 36 healthy human
subjects
80% equivalent area under the curve
2001 American Society of Transplantation
Scientific Forum

Specifically addressed cyclosporine generic
formulations
Am J Transplant.2003;3:1211-1215
Historical Concern

Taber et al.

Cyclopsorine microemulsion products


Gengraf® (n=88) vs Neoral® (n=100)
Retrospective review

Acute rejection within 6 months of transplant


Second rejection


39% versus 25%, p=0.04
19% versus 8%, p=0.02
Higher variability in cyclosporine concentrations in
patients treated with Gengraf®
Transplantation.2005;80:1633-1635
New Generics

Tacrolimus


More predictable kinetics, better correlation with
AUC
Mycophenolic Acid


Two formulations currently
Unpredictable kinetics
MUSC Transplant PharmDs


Nicole A. Weimert, Pharm.D., BCPS
Clinical Pharmacy Specialist, Solid Organ
Transplant
Clinical Assistant Professor of Pharmacy
MUSC Department of Pharmacy Services
150 Ashley Ave
Charleston, SC 29425
(843) 792-3702 office
(843) 792-0566 fax
Dave Taber, PharmD, BCPS
Pharmacy Clinical Specialist - Transplant
Clinical Assistant Professor, SCCM
MUSC Department of Pharmacy Services
PO Box 250584
150 Ashley Avenue - 6th floor RTA
Charleston, SC 29425
Tel: (843) 792-8532
Fax: (843) 792-0566
“Oh great! We have a transplant
patient on our service”
Transplant for the Non-Transplant
Clinician
Nicole A. Weimert, PharmD, BCPS
Clinical Specialist, Solid Organ Transplantation
Assistant Clinical Professor, USC-COP
Medical University of South Carolina
Department of Pharmacy Services