1. “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

2. 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 non-transplant related issues

3. Immunology 101

4. Maintaining the Balance
Infection
Malignancy
Life Saving Procedure
Graft Function

5. 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

6. Cells of the Immune System
Antigen Presenting Cell
T cell Y Y Y Y
B cell Y Y Y

7. 9 steps……

8. The antigen presenting cell (APC) envelops circulating antigen
The antigen is processed within the APC into small protein fragments called peptides
APC’s envelope circulating antigens of the transplanted kidney within the body and the transplanted kidney

9. The peptides bind to human leukocyte antigen (HLA)
APC
The peptides bind to human leukocyte antigen (HLA)
The HLA/peptide complex migrate to the cell membrane of the APC

10. The APC presents the HLA/peptide complex to T cells
T cell receptors (TCR) on T cells recognize a specific HLA/peptide
T cell activate and initiate proliferation via a complex pathway
TCR
CD3
T cell

11. APC A T Cell cytokines IL-2 R HLA IL-2 IL-2 IL-2 Calcineurin TCR NF-AT
Binding of the TCR to the HLA/peptide complex A
NF-AT
DNA synthesis
IL-2 gene
T Cell

12. B cell activation Y Y Y Y Y Y Y
cytokines Y
B cell Y
Plasma cell
T cell Y Y Y Y Y
Cytokines activate and induce proliferation of B cells
B cells produce antibodies specific to the antigen

13. Rejection Y Y Y Y Y Y Y T cells directly attack the transplanted organ
B cell Y Y Y Y Y
T cells directly attack the transplanted organ
Antibodies produced by B cells lead to the destruction to the transplanted organ

14. 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

21. Review of Drug Disease State Interactions
Common Issues
Review of Drug Disease State Interactions

22. Question: This transplant patient was admitted for urosepsis
Question: This transplant patient was admitted for urosepsis. What should we do with their immuosuppression?

23. 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

24. 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

25. 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

26. What should we stop first?
Pick the agent that has the broadest spectrum of activity:
Corticosteroids
Mycophenolic Acid
Tacrolimus
Cyclosporine

27. What should we stop first?
Pick the agent that has the broadest spectrum of activity:
Corticosteroids
Mycophenolic Acid
Tacrolimus
Cyclosporine
Why can’t we just stop the corticosteroids?

28. Adrenal Axis Suppresion
Exposure to corticosteroids
for < 3 weeks rarely induces clinical adrenal suppression
Kronenberg: Williams Textbook of Endocrinology, 11th ed.

29. Question: Supplementation
Do transplant recipients on chronic steroids need supplemental doses during periods of acute stress (surgery, infection)?
YES or NO

30. 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:

31. 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:
J Am Coll Surg. 1995;180:

32. Current Evidence Corticosteroids in Septic Shock: Meta-Analysis
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:
BMJ 2004;329:

33. 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

34. Question: We performed bowel surgery on this transplant patient, how do we convert their immunosuppression to IV?

35. Question What is the PO to IV conversion for calcineurin inhibitors?
1:1
2:1
3:1
4:1

36. Question What is the PO to IV conversion for calcineurin inhibitors?
1:1
2:1
3:1
4:1

37. Conversion Considerations
Simple answer:
3:1
Tacrolimus.package insert.Astellas.Revised April 2006
Int J Clin Pharmacol Ther. 2004;42:

38. 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:

39. 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:

40. Conversion Considerations
Infusion
Continuous versus intermittent q 12 hours
Hypertension
Renal insufficiency
Tubing
Must use non-PVC tubing
Drawing levels - will contaminate tubing
Central lines, port-a-cath
Am J Health System Pharm.2008;65:

41. 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

42. Question: So we have this transplant patient on cyclosporine
Question: So we have this transplant patient on cyclosporine. What level should this patient be at?

43. Appropriate Level Several variables: Center Patient Organ
Time since transplant
Rejection history
Current clinical situation
Concurrent immunosuppression

44. Appropriate Level Several variables: Center Patient Organ
Time since transplant
Rejection history
Current clinical situation
Concurrent immunosuppression
Contact the patient’s transplant coordinator

45. Question: So we have this transplant patient on cyclosporine
Question: So we have this transplant patient on cyclosporine. How often should we be getting levels?

46. Measuring Levels Compliance Impending drug interactions Efficacy
Measure of allograft function
Toxicity
Elevated levels may induce renal artery vasoconstriction
Liver insufficiency
Increased levels
Diarrhea
Pediatr Transplant. 2005;9:
Am J Transplant. 2005;5:

47. Question: We have to start an azole antifungal agent
Question: We have to start an azole antifungal agent. How should we adjust their medicines and when will we see the effect?

48. Question
What is the primary mechanism of fluconazole associated with elevations in the calcineurin inhibitor level?
Liver CYP450 inhibition
Intestinal P-glycoprotein inhibition
Protein binding
Intestinal CYP450 inhibition

49. Question
What is the primary mechanism of fluconazole associated with elevations in the calcineurin inhibitor level?
Liver CYP450 inhibition
Intestinal P-glycoprotein inhibition
Protein binding
Intestinal CYP450 inhibition

50. 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:
Eur J Clin Pharmacol. 2008;64:89-91

51. Azole Antifungal and Calcineurin Inhibitor
If patient has had stable levels
Reduce dose in half
Onset of interaction
24 to 72 hours
Prolonged
Magnitude of interaction for inhibitor
Increased with oral administration

52. * Indicates potent inhibitor or inducer
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 concentration and total AUC of the IS
Either prospectively decrease the IS dose or monitor trough concentrations more closely and adjust doses accordingly
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 concentration 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
Avoid concomitant administration with IS and monitor trough concentrations
azathioprine
allopurinol
Inhibits metabolism by inhibiting xanthine oxidase
Increases the concentration and total AUC of azathioprine
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

53. Question: Can we cath a patient with a kidney transplant who had marginal renal function?

54. 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:
J Am Soc Nephrol 1998; 9:S16

55. Contrast Induced Nephropathy
Definition:
Absolute (Scr≥0.5 mg/dL) or relative (≥25%) increase in after exposure to contrast
Occurs within 24 to 48 hours following exposure
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

56. 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

57. Pre-Treatment for All Transplant Recipients

58. Question: What about the generic immunosuppressants?

59. Generic Use in Transplant
Generic Timeline
Product
Patent
Expired
Generic Approved
Generic Use in Transplant
Imuran® (Azathioprine)
1979
1996
No difference in outcomes
Neoral® (Cyclosporine)
1995
Increased rejection rates
Prograf®
(Tacrolimus)
April 2008
Pending NDAs
Unknown
Cellcept® (mycophenolate mofetil)
May 2009

60. 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:

61. Historical Concern Taber et al. Cyclopsorine microemulsion products
Gengraf® (n=88) vs Neoral® (n=100)
Retrospective review
Acute rejection within 6 months of transplant
39% versus 25%, p=0.04
Second rejection
19% versus 8%, p=0.02
Higher variability in cyclosporine concentrations in patients treated with Gengraf®
Transplantation.2005;80:

62. New Generics Tacrolimus Mycophenolic Acid
More predictable kinetics, better correlation with AUC
Mycophenolic Acid
Two formulations currently
Unpredictable kinetics

64. 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 (843) office (843) fax
Dave Taber, PharmD, BCPS Pharmacy Clinical Specialist - Transplant Clinical Assistant Professor, SCCM MUSC Department of Pharmacy Services PO Box Ashley Avenue - 6th floor RTA Charleston, SC Tel:  (843) Fax:  (843)

65. “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