Immunosuppression in Transplantation



Immunosuppression in Transplantation


Holly B. Meadows

Michael S. Boger



INTRODUCTION

Maintenance immunosuppression for solid organ transplant recipients has been utilized for over 50 years. Initially, azathioprine and corticosteroids were the mainstay of immunosuppression until the approval of calcineurin inhibitors in the 1980s and 1990s. Since the mid-1990s, several immunosuppressants have been approved, including mycophenolic acid, the mammalian target of rapamycin inhibitors, sirolimus and everolimus, and the newly approved belatacept. While immunosuppression is vital to allograft survival, all available agents are associated with significant adverse effects, including infection and malignancy. Transplant health care providers struggle to find the balance between efficacy and tolerability regarding immunosuppression.1,2,3,4,5


CALCINEURIN INHIBITORS: INHIBIT INTERLEUKIN-2 PRODUCTION


Mechanism of Action



  • Prevent interleukin-2 production and therefore cytotoxic T-cell activation1,2,3


Efficacy



  • Tacrolimus is considered a more potent immunosuppressant than cyclosporine.3,6


  • Efficacy trials between the two agents have shown that tacrolimus decreases rates of acute rejection at 1 year after transplant. However, long-term outcome data between cyclosporine and tacrolimus have not shown a clear benefit of one over the other in regard to patient and allograft survival.6,7,8


Dosing and Monitoring



  • Dosing is transplant center-specific. Guidelines are displayed in Table 45-1.2,9


  • Calcineurin inhibitors are usually monitored by 12-hour trough levels. Target trough levels are transplant center-specific and dependent on a variety of factors, including time since transplant, organ transplanted, renal function, and concomitant immunosuppression.2,3,9


Drug Interactions and Adverse Effects



  • Calcineurin inhibitors are metabolized in the liver and are substrates for the cytochrome P450 3A4 isoenzyme and P-glycoprotein.


  • Significant drug interactions are displayed in Table 45-2.


  • Adverse effects are displayed in Table 45-3 and include nephrotoxicity, infection, and malignancy.1,2,3,9









    Table 45-1 Immunosuppression Dosing and Monitoring






















































    Immunosuppressant

    Standard Dosing

    IV:PO

    Typical Target Trough Levels


    Cyclosporine

    1.5-2.5 mg/kg P.O. b.i.d.

    ˜1:3

    50-200 ng/mL


    Tacrolimus

    1 mg P.O. b.i.d. 0.02-0.05 mg/kg b.i.d.

    ˜1:4

    5-12 ng/mL


    Azathioprine

    1-4 mg/kg/day

    ˜1:1

    N/A


    Mycophenolate mofetila

    1,000-1,500 mg P.O. b.i.d.

    ˜1:1

    Therapeutic drug monitoring is controversial.


    Sirolimus

    2-5 mg daily (May give loading dose)

    N/A 5-15 ng/mL


    Everolimus

    0.5-0.75 mg P.O. b.i.d.

    N/A 3-8 ng/mL


    Belatacept

    10 mg/kg days 1b and 5c

    N/A

    N/A

    10 mg/kg after 2 and 4 wk

    10 mg/kg after 8 and 12 wk

    5 mg/kg after 16 wk and every 4 wk thereafter



    a Mycophenolate sodium 720 mg is equivalent to mycophenolate mofetil 1,000 mg. (There is no IV formulation of mycophenolate sodium)

    b To be given prior to organ reperfusion

    c ˜96 hours after dose 1









    Table 45-2 Common Drug Interactions with Calcineurin Inhibitors and mTOR Inhibitors































    Increase Concentrations (CYP3A4 Inhibitor)

    Decrease Concentrations (CYP3A4 Inducer)


    “Azole” antifungals, including voriconazole, fluconazole, itraconazole, and ketoconazole

    Phenytoin


    Diltiazem

    Carbamazepine


    Verapamil

    Phenobarbital


    Amiodarone

    Rifampin


    Clarithromycin

    Rifabutin


    Erythromycin

    St. John’s wort


    Danazol


    Protease Inhibitors


    Grapefruit Juice










    Table 45-3 Common and Serious Adverse Effects of Immunosuppressants



























    Immunosuppressant

    Adverse Effects


    Cyclosporine

    Nephrotoxicity, neurotoxicity, hyperglycemia, hyperkalemia, hypomagnesemia, hyperuricemia, hyperlipidemia, hypertension, hirsutism, gingival hyperplasia, infection, malignancy


    Tacrolimus

    Nephrotoxicity, neurotoxicity, hyperglycemia, hyperkalemia, hypomagnesemia, hyperuricemia, hyperlipidemia, hypertension, alopecia, infection, malignancy


    Azathioprine

    Leukopenia, anemia, thrombocytopenia, gastrointestinal disturbances, pancreatitis, liver toxicity, alopecia, skin cancers (likely related to overall level of immunosuppression)


    Mycophenolate mofetil/sodium

    Nausea, vomiting, diarrhea, abdominal pain, leukopenia, anemia, thrombocytopenia, malignancy, increased tissue-invasive cytomegalovirus (CMV) infection, increased risk of progressive multifocal leukoencephalopathy (PML)


    Sirolimus/Everolimus

    Hyperlipidemia, delayed would healing, proteinuria, anemia, thrombocytopenia, gastrointestinal disturbances, pneumonitis, infections


    Corticosteroids

    Hyperglycemia, osteoporosis, infection, mood disturbances, psychosis, fluid retention, weight gain, hypertension, cataracts, peptic ulcers


    Belatacept

    Posttransplant lymphoproliferative disorder (increased in EBV seronegative recipients), infusion reactions (rare), infection



CYCLOSPORINE (SANDIMMUNE, NEORAL, GENGRAF)

Cyclosporine products are not bioequivalent. Practitioners should always confirm cyclosporine products with patients and continue them on the same formulation. If this is not possible, cyclosporine concentrations should be monitored closely.3,9

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Jun 22, 2016 | Posted by in INFECTIOUS DISEASE | Comments Off on Immunosuppression in Transplantation

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