Presentation on theme: "Nicole A. Weimert, PharmD, BCPS"— Presentation transcript:
1 “Oh great! We have a transplant patient on our service” Transplant for the Non-Transplant Clinician Nicole A. Weimert, PharmD, BCPSClinical Specialist, Solid Organ TransplantationAssistant Clinical Professor, USC-COPMedical University of South CarolinaDepartment of Pharmacy Services
2 ObjectivesProvide a brief review of transplant immunology and immunosuppressionReview common drug, disease, immunosuppression interactionsDescribe situations and solutions related to administration of immunosuppressantsDiscuss common case-based scenarios related to the presentation of transplant recipients with non-transplant related issues
8 The antigen presenting cell (APC) envelops circulating antigen The antigen is processed within the APC into small protein fragments called peptidesAPC’s envelope circulating antigens of the transplanted kidney within the body and the transplanted kidney
9 The peptides bind to human leukocyte antigen (HLA) APCThe 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/peptideT cell activate and initiate proliferation via a complex pathwayTCRCD3T 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 complexANF-ATDNA synthesisIL-2 geneT Cell
12 B cell activation Y Y Y Y Y Y Y cytokinesYB cellYPlasma cellT cellYYYYYCytokines activate and induce proliferation of B cellsB cells produce antibodies specific to the antigen
13 Rejection Y Y Y Y Y Y Y T cells directly attack the transplanted organ B cellYYYYYT cells directly attack the transplanted organAntibodies produced by B cells lead to the destruction to the transplanted organ
14 The Immune SystemSpecificity : distinguish between non-cross reacting antigens.Memory: quick and vigorous response to a subsequent but similar pathogen or antigenMobility: 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 IssuesReview 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 systemsBe aggressive with initial treatmentConsider the consequences of organ dysfunction if immunosuppression is heldHow far out from transplant
24 Infection and Transplant Facts:Inefficient immune systemsConsider the consequences of organ dysfunction if immunosuppression is heldHeart versus KidneyHow far out from transplant
25 Infection and Transplant Facts:Inefficient immune systemsConsider the consequences of organ dysfunction if immunosuppression is heldHow far out from transplantRisk of acute rejection decreases further out from transplantHave they had a recent rejection episodeAre they compliant
26 What should we stop first? Pick the agent that has the broadest spectrum of activity:CorticosteroidsMycophenolic AcidTacrolimusCyclosporine
27 What should we stop first? Pick the agent that has the broadest spectrum of activity:CorticosteroidsMycophenolic AcidTacrolimusCyclosporineWhy can’t we just stop the corticosteroids?
28 Adrenal Axis Suppresion Exposure to corticosteroidsfor < 3 weeks rarely induces clinical adrenal suppressionKronenberg: 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)?DEPENDSConcerns:Impaired wound healingFurther immunosuppressionTransplantation. 1991;51:
31 Historical Evidence Bromberg et al. Prospective evaluation of kidney transplant recipients admitted with physiological stressSurgery, sepsis, metabolic abnormalitiesN=40Did not receive supplemental steroid dosesRemained on admission dose (5 to 10 mg/day)MeasurementsSerum 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 benefitCorticosteroid Therapy of Septic Shock (CORTICUS)Efficacy and safety of low-dose hydrocortisone therapy in septic shockMulti-center, double blind, randomized, placebo controlledInclusion criteria: adult, sepsis within 72 hrsExclusion criteria: chronic immunosuppression or steroid useNo change in 28 day mortalityN Engl J Med. 2008;358:BMJ 2004;329:
33 Recommendations: Infected Transplant Recipients Assess the severity of illness and relative risk for acute rejectionDiscontinue adjunctive agent and minimize other immunosuppressionSupplement 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? 1:12:13:14:1
36 Question What is the PO to IV conversion for calcineurin inhibitors? 1:12:13:14:1
38 Conversion Considerations Simple answer:3:1Why this does not work:Bioavailability:Tacrolimus : <30%Trough concentrations have good correlation with ACU (r2=0.93)Cyclosporine : erratic, formulation dependentTacrolimus.package insert.Astellas.Revised April 2006Int J Clin Pharmacol Ther. 2004;42:
39 Conversion Considerations Simple answer:3:1Why this does not work:Bioavailability:Tacrolimus : <30%Trough concentrations have good correlation with ACU (r2=0.93)Cyclosporine : erratic, formulation dependentRace differences:Oral bioavailability in African-Americans is 20 and 50% lower than in CaucasiansTacrolimus.package insert.Astellas.Revised April 2006Int J Clin Pharmacol Ther. 2004;42:
40 Conversion Considerations InfusionContinuous versus intermittent q 12 hoursHypertensionRenal insufficiencyTubingMust use non-PVC tubingDrawing levels - will contaminate tubingCentral lines, port-a-cathAm J Health System Pharm.2008;65:
41 Recommendations: Converting Calcineurin Inhibitors to IV Use a designated lineWhen in doubt start lowEmpiric weight based dosingTacrolimus 0.01 – 0.03 mg/kg/dayCyclosporine 3 – 5 mg/kg/dayUse conversion“Soft” maximum doses for initiationTacrolimus >4 mg in 24 hoursCyclosporine > 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 transplantRejection historyCurrent clinical situationConcurrent immunosuppression
44 Appropriate Level Several variables: Center Patient Organ Time since transplantRejection historyCurrent clinical situationConcurrent immunosuppressionContact 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 functionToxicityElevated levels may induce renal artery vasoconstrictionLiver insufficiencyIncreased levelsDiarrheaPediatr 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 QuestionWhat is the primary mechanism of fluconazole associated with elevations in the calcineurin inhibitor level?Liver CYP450 inhibitionIntestinal P-glycoprotein inhibitionProtein bindingIntestinal CYP450 inhibition
49 QuestionWhat is the primary mechanism of fluconazole associated with elevations in the calcineurin inhibitor level?Liver CYP450 inhibitionIntestinal P-glycoprotein inhibitionProtein bindingIntestinal CYP450 inhibition
51 Azole Antifungal and Calcineurin Inhibitor If patient has had stable levelsReduce dose in halfOnset of interaction24 to 72 hoursProlongedMagnitude of interaction for inhibitorIncreased with oral administration
52 * Indicates potent inhibitor or inducer ImmunosuppressantInteracting DrugsMechanismConsequenceClinical Managementcalcinuerin inhibitors (cyclosporine and tacrolimus) and sirolimusclarithromycin*, 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 intestinesIncrease the concentration and total AUC of the ISEither prospectively decrease the IS dose or monitor trough concentrations more closely and adjust doses accordinglycarbamazepine*, dexamethasone, phenobarbital*, phenytoin*, St. John’s Wort*, rifampin*, rifabutin*, efavirenz*, nevirapine*, nafcillin, clindamycinInduce CYP450 3A4 isoenzyme in the liver and intestinesDecrease the concentration and total AUC of the ISEither prospectively increase the IS dose or monitor trough concentrations more closely and adjust doses accordinglycalcinuerin inhibitors (cyclosporine and tacrolimus), sirolimus, and mycophenolate mofetilcholestyramine, colestipol, probucol, sevelamer, antacids (magnesium and aluminum containing)**, iron containing products**Bind to IS and prevents absorptionAvoid concomitant administration with IS and monitor trough concentrationsazathioprineallopurinolInhibits metabolism by inhibiting xanthine oxidaseIncreases the concentration and total AUC of azathioprineAvoid 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 event3.5% to 5%50 fold higher than the general populationTransplantation 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 contrastOccurs within 24 to 48 hours following exposurePeak 3 to 5 days with a return to baselineEtiologyDirect toxicity to renal tubular epithelium, oxidative stress, and ischemic injuryCatheterization and Cardiovascular interventions.2008;71:62-72
56 Clinical Pearls Do not withhold life-saving treatment Reversible damage from contrastCan be attenuated with adequate hydrationOther pharmacological interventions may decrease the length and severity of injuryHydrationN-acetylcysteineSodium bicarbonate
58 Question: What about the generic immunosuppressants?
59 Generic Use in Transplant Generic TimelineProductPatentExpiredGeneric ApprovedGeneric Use in TransplantImuran® (Azathioprine)19791996No difference in outcomesNeoral® (Cyclosporine)1995Increased rejection ratesPrograf®(Tacrolimus)April 2008Pending NDAsUnknownCellcept® (mycophenolate mofetil)May 2009
60 The Ongoing Discussion in Transplant Circles Controversy over the current FDA approval process for generic medicationBioequivalence study – 18 – 36 healthy human subjects80% equivalent area under the curve2001 American Society of Transplantation Scientific ForumSpecifically addressed cyclosporine generic formulationsAm J Transplant.2003;3:
61 Historical Concern Taber et al. Cyclopsorine microemulsion products Gengraf® (n=88) vs Neoral® (n=100)Retrospective reviewAcute rejection within 6 months of transplant39% versus 25%, p=0.04Second rejection19% versus 8%, p=0.02Higher variability in cyclosporine concentrations in patients treated with Gengraf®Transplantation.2005;80:
62 New Generics Tacrolimus Mycophenolic Acid More predictable kinetics, better correlation with AUCMycophenolic AcidTwo formulations currentlyUnpredictable 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) faxDave 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, BCPSClinical Specialist, Solid Organ TransplantationAssistant Clinical Professor, USC-COPMedical University of South CarolinaDepartment of Pharmacy Services