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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,

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Presentation on theme: "“Oh great! We have a transplant patient on our service” Transplant for the Non-Transplant Clinician Nicole A. Weimert, PharmD, BCPS Clinical Specialist,"— Presentation transcript:

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 Graft Function Infection Malignancy Life Saving Procedure

5 Transplanted Organ “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 = Antigen

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

7 9 steps……

8 1. The antigen presenting cell (APC) envelops circulating antigen 2. The antigen is processed within the APC into small protein fragments called peptides APC = Antigen

9 3. The peptides bind to human leukocyte antigen (HLA) 4. The HLA/peptide complex migrate to the cell membrane of the APC HLA APC

10 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 APC T cell TCR CD3

11 T Cell Calcineurin NF-AT IL-2 gene DNA synthesis TCR APC IL-2 A IL-2 R cytokines HLA IL-2

12 B cell activation 8. Cytokines activate and induce proliferation of B cells 9. B cells produce antibodies specific to the antigen T cell cytokines B cell Plasma cell Y Y Y Y Y Y Y Y Y Y Y

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

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

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21 Common Issues Review of Drug Disease State Interactions

22 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: A. Corticosteroids B. Mycophenolic Acid C. Tacrolimus D. Cyclosporine

27 What should we stop first? Pick the agent that has the broadest spectrum of activity: A. Corticosteroids B. Mycophenolic Acid C. Tacrolimus D. 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? A. 1:1 B. 2:1 C. 3:1 D. 4:1

36 Question What is the PO to IV conversion for calcineurin inhibitors? A. 1:1 B. 2:1 C. 3:1 D. 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 (r 2 =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 (r 2 =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. 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. 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 Increased levels Pediatr Transplant. 2005;9: Am J Transplant. 2005;5:

47 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? A. Liver CYP450 inhibition B. Intestinal P-glycoprotein inhibition C. Protein binding D. Intestinal CYP450 inhibition

49 Question What is the primary mechanism of fluconazole associated with elevations in the calcineurin inhibitor level? A. Liver CYP450 inhibition B. Intestinal P-glycoprotein inhibition C. Protein binding D. 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 Immunosuppressant Interacting DrugsMechanismConsequenceClinical 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 azathioprineallopurinol 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

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

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 More predictable kinetics, better correlation with AUC Mycophenolic Acid Two formulations currently Unpredictable kinetics

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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


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