Transplant Pharmacology



Transplant Pharmacology


Christopher R. Ensor, PharmD, BCPS

Vicki McCalmont, RN, MS, ANP-BC, CNS, CCTC



I. INTRODUCTION

A. Overview



  • The use of immunosuppressive agents has evolved over the years, improving transplant opportunities, longevity, and quality of life.


  • Immunosuppressing agents are designed to alter the immune system before, during, and after transplantation. The actions of these agents are specific to immune mechanisms associated with rejection.



    • Desensitizing agents are used prior to transplantation to reduce/remove circulating antibodies, thereby allowing highly sensitized patients to have a successful transplant.1,2


    • Induction therapy is typically used for patients at high risk for cellular or antibody-mediated acute rejection or patients with impaired renal function that need delayed or calcineurin inhibitor-free immunosuppression maintenance therapy.3,4,5,6,7,8,9,10


    • Maintenance therapy begins at the time of transplant and typically starts with triple therapy and is titrated to the patient’s need.


    • Rejection treatment is targeted to the type of rejection. Antibody-mediated rejection (AMR) and cellular rejection are treated according to the severity of rejection and may range from adjusting the maintenance immunosuppressive regimen, pulse steroids, use of antibodies (polyclonal or monoclonal), plasmapheresis, and intravenous immune globulin (IVIG).11,12,13,14,15,16,17,18,19,20


  • Risks associated to immunosuppression include rejection, infection, and cancer.



    • Inadequate immunosuppression places the patient at risk for rejection. Rejection may occur when



      • Immunosuppressive doses are decreased too rapidly.


      • Drug interactions between immunosuppressants and other drugs or foods lower immunosuppressive drug levels.


      • Patients are nonadherent with their medications (intentional or unintentional).



    • Overimmunosuppression places the patient at risk for infection and malignancy due to the weakened immune system.


    • Antimicrobial agents are commonly used to prevent or treat infection, for example:



      • Antifungal agents are typically used to prevent oral candidiasis.


      • Antibacterial agents are typically used for Pneumocystis carinii (jiroveci) pneumonitis (PCP) or toxoplasmosis (Toxoplasma gondii) prophylaxis.


      • Antiviral agents are used for prevention or treatment of common posttransplant viral infections, such as



        • Cytomegalovirus (CMV)


        • Herpes simplex virus (HSV)


        • Epstein-Barr virus (EBV)

B. Immunosuppressive agents



  • Target-specific mechanisms of immune activation (Figure 4-1)


  • Have unique pharmacological and toxicity profiles



    • Used to produce a potent state of immunosuppression


    • Used in combination to maximize efficacy and minimize short- and long-term toxicity


  • Can be classified under two major categories:



    • Immunosuppressive antibody therapy may be used for desensitization, induction, or treatment of rejection.21,22,23



      • Polyclonal antibodies:



        • Used for induction and treatment of acute rejection


        • Rabbit antithymocyte globulin (rATG)



          • Thymoglobulin


          • ATG-Fresenius


        • Equine antithymocyte globulin



          • Atgam


      • Antilymphocyte monoclonal antibodies include the following:



        • Alemtuzumab (Campath-1H) is a monoclonal antibody against the CD52 lymphocyte (both T and B cells), anti-CD20 antibodies


        • Rituximab (Rituxan) is a monoclonal antibody that depletes CD20 positive B cells


        • Eculizumab (Soliris) is a monoclonal antibody directed against the C5 fragment in the complement cascade



          • Used for desensitization and antibody-mediated rejection


      • Protease inhibitors: Bortezomib (Velcade)



        • Used for desensitization and antibody-mediated rejection


      • Interleukin-2 (IL-2) receptor antibodies: Basiliximab (Simulect)



        • May be used off-label for induction and antibody-mediated rejection


    • Maintenance immunosuppression therapy



      • These agents are classified based on their mechanism of actions into24,25,26,27,28,29,30



        • Calcineurin inhibitors (CNI)


        • Antiproliferative agents


        • Corticosteroids


        • Proliferation signal inhibitors


        • Costimulation inhibitors







FIGURE 4-1 Mechanism of action of immunosuppressive drugs. Typically, one calcineurin inhibitor, one antiproliferative, or proliferation signal inhibitor, and a corticosteroid are used in combination. Monoclonal and polyclonal antibodies are used to delay the use of a calcineurin inhibitor or to treat rejection. The calcineurin inhibitors, cyclosporine (CsA) and tacrolimus (Tac), bind to cyclophilin (CpN) and FK-binding protein (FKBP), respectively, and then inhibit calcineurin-dependent dephosphorylation of NFAT. Mycophenolic acid (MPA), the active derivative of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase-dependent purine biosynthesis. Azathioprine (AZA) is metabolized to 6-mercaptopurine (6-MP), which inhibits cell cycling by providing a “false” purine. Sirolimus (SRL) and everolimus (ERL) bind to FKBP and inhibit molecular target of rapamycin (mTOR), preventing cyclin-dependent kinase (CDK)-mediated cell cycling. Antithymocyte globulins (ATG) bind to T-cell surface antigens (e.g., CD2, CD4, or CD5) enabling lymphocyte opsonization by the reticuloendothelial system (RES). Anti-CD25 monoclonal antibodies (MAB) like basiliximab prevent IL-2 and IL-2 receptor engagement and are not used to treat rejection. Corticosteroids act by binding to corticosteroid receptors, negatively impact glucocorticoid response elements (GRE), and decrease production and action of multiple interleukins. Abbreviations: CD, cluster determinant; MHC, major histocompatibility class; MAP, mitogen-activated protein; AP-1, activating protein 1; NFκB, nuclear factor κB; mRNA, messenger ribonucleic acid.


II. IMMUNOSUPPRESSIVE ANTIBODY THERAPY

A. In the past decade, transplantation across incompatible barriers has become necessary due to the organ shortage and challenges with highly sensitized patients. The use of desensitization protocols using newer antibody agents, plasmapheresis, and IVIG has allowed programs to
successfully transplant patients who were deemed not-transplantable in the past. In addition, antibody therapy and/or IVIG have been used as “induction therapy” immediately after transplant in highly sensitized patients or those who need delayed initiation of nephrotoxic immunosuppressant drugs. Induction therapy is considered a form of intense immunosuppression that facilitates early graft acceptance. Lastly, antibody therapy can be used for treatment of severe rejection episodes.

B. Protocols for treatment are evolving as a result of improved technology for the detection of human leukocyte antigen (HLA) antibody and panelreactive antibody (PRA) testing prior to transplant and donor-specific antibody (DSA) testing after transplant.



  • PRA and HLA testing prior to transplant identify highly sensitized patients who may benefit from desensitization therapy to reduce their antibody load and prepare them for a successful transplant. Prior to the availability of this testing and subsequent antibody reduction therapy, these patients were never able to get a transplant due to the extremely high risk of hyperacute rejection.1,2


  • Posttransplant, DSA testing monitors the immune response and facilitates the early detection of donor antibodies. This early detection allows for immunosuppressive medication adjustments to prevent AMR.



    • Transplant center protocols may include scheduled DSA testing at regular intervals for rejection prevention.


    • DSA testing may also be used to



      • Detect suspected acute antibody-mediated rejection and assess severity


      • Measure antibody presence after a course of treatment for rejection

C. Desensitization therapy



  • Over the past decade, the advent of desensitization therapy has increased transplant opportunities for patients referred for all types of solid organ transplantation.1,2



    • Prior to these desensitization protocols, if a transplant candidate had an antibody specific to a potential donor’s HLA, that donor was declined due to the risk for hyperacute rejection.


    • Desensitization therapies aim to remove circulating antibodies, thereby affording a candidate an opportunity to potentially undergo transplantation with a negative crossmatch.


    • Timing of this therapy varies based upon donor availability.



      • While on the transplant waiting list, highly sensitized patients may receive treatment to remove circulating antibodies, thereby increasing the number of acceptable donor offers.


      • Preoperative or perioperative desensitization is given to candidates with an elevated PRA ≥30%, multiple HLA mismatches, or positive crossmatch with a medically urgent need.2


  • Desensitization agents used (Table 4-1)13,14,15,16



    • Plasmapheresis17,18



      • Always done prior to the administration of IVIG or antibody therapy because plasmapheresis removes IVIG and other monoclonal antibodies during the plasma exchange.


    • IVIG16,17,18


    • Antilymphocyte monoclonal antibodies:



      • Alemtuzumab (Campath-1H) is a monoclonal antibody against the CD52 lymphocyte (both T and B cells), anti-CD20 antibodies.4,5









        TABLE 4-1 Desensitization/Antirejection therapies

































































        Therapy

        Use

        Class

        Mechanism of Action

        Adverse Reactions

        Comments


        Plasmapheresis

        D


        AMR

        Procedure

        Removal of circulating antidonor antibodies from peripheral blood

        Hypotension, arrhythmias

        Takes 1-3 h for a plasma exchange using a dialysis catheter


        IVIG

        D


        AMR

        Pooled polyclonal antibodies

        Repletes immunoglobulins removed by plasmapheresis, reduces allosensitization and ischemic-perfusion reactions through B-cell apoptosis

        Infusion reaction


        Headache

        Premedicate with acetaminophen.


        Given by slow infusion


        Half life is 3-4 wk


        May follow plasmapheresis or antibody therapy


        Eculizumab (Soliris)

        D


        AMR

        Monoclonal antibody

        Complement C5 inhibitor to prevent complement-mediated rejection

        Infusion reaction, headache, hypertension, leukopenia, infection

        Complement is the final step in the AMR pathway. Patients refractory to other monoclonal antibody therapies may respond to eculizumab


        Rituximab (Rituxan)

        D


        I


        AMR

        Monoclonal antibody

        Binds to CD20 on B cells to deplete circulating B cells

        Infusion reaction (fevers, rigors, pain), risk for serious infection, PML, SJS

        Premedicate with acetaminophen, antihistamine, and steroids


        Given by IV infusion, slowly


        PCP and antiviral prophylaxis may be given up to 12 m postdose


        Alemtuzumab (Campath-1H)

        AMR

        Monoclonal antibody

        Binds to CD52 on mature lymphocytes and depletes T and B cells

        Infusion reaction, fevers, rash, nausea, hypotension, cytopenia infection: CMV

        Premedicate with acetaminophen, antihistamine


        PCP and antiviral prophylaxis may be given for a minimum of 2 mo postdose


        Bortezomib (Velcade)

        D


        AMR

        Protease inhibitor

        Protease inhibitor. Promotes apoptosis in plasma cells, which generate antibodies

        Bone marrow suppression, neuropathy, hypotension, GI toxicity

        Premedicate with antiemetics and antidiarrheals


        Reduce dose if the patient has moderate hepatic dysfunction


        Basiliximab (Simulect)

        I

        Monoclonal antibody

        Blocks the IL-2 receptor thus preventing T-cell replication (reducing immune response) and B-cell activation (reducing antibodies)

        Infusion reaction, agranulocytosis, edema headache, GI toxicity

        Is typically give as IV infusion over 20-30 min


        Monitor labs: (↑Cr, ↑K, ↓ Phos)


        Infusion reactions may include fever, rigors, hypotension, tachycardia, arrhythmias, dyspnea, bronchospasms, wheezing, respiratory failure, rash, or other hypersensitivity reaction such as anaphylaxis. GI toxicity may include nausea, vomiting, dyspepsia, diarrhea, constipation, and abdominal pain.


        D, desensitization; AMR, antibody-mediated rejection; I, Induction; IV, intravenous; PCP, Pneumocystis carinii pneumonia; CMV, cytomegalovirus; GI, gastrointestinal; IL, interleukin; Cr, Creatinine; K, Potassium; Phos, phosphorus.


        Kim M, Martin ST, Townsend RK, et al. Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis and treatment options. Pharmacotherapy. 2014;34(7):733-744; Hendrikx TK, Klepper M, Ijzermans J, et al. Clinical rejection and persistent immune regulation in kidney transplant patients. Transpl Immunol. 2009;21(3):129-135; Colaneri J. An overview of transplant immunosuppression: history, principles, and current practices in kidney transplantation. Nephrol Nurs J. 2014;41(6):549-561; Jordan SC, Totoda M, Kahwaii J, et al. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011;11(2):196-202.




      • Rituximab (Rituxan) is a monoclonal antibody that depletes CD20 positive B cells.8,17


      • Eculizumab (Soliris) is a monoclonal antibody directed against the C5 fragment in the complement cascade.9,10,11



        • Used for desensitization and treatment of AMR.


        • To date, the results of small studies are controversial with regard to the efficacy of eculizumab in treating refractory AMR.9,10 Therefore, it is too soon to determine the true benefit in all solid organ transplant recipients without additional data.


    • Protease inhibitor: bortezomib (Velcade)



      • Used for desensitization and treatment of AMR11,12,15


    • Interleukin-2 (IL-2) receptor monoclonal antibody: basiliximab (Simulect)22


  • Any of the above agents may be used alone or in combination to deplete circulating antibodies, to deplete antibody-producing cells, and to block antibodies from binding to the epithelium (with subsequent rejection), thus protecting the allograft from damage.13,14,15,16



    • In addition to desensitization therapy, the above agents may also be used for the treatment of AMR. See Table 4-1 for desensitization and antirejection therapies.13,14,15,16


    • Refer to your transplant program protocol for the timing and dosing of the above agents.

D. Induction or acute rejection immunosuppression therapy



  • Induction immunosuppression agents are used immediately posttransplant to neutralize the initial robust T-cell-mediated immune response. These agents reduce the risk of rejection by depleting T cells and/or interrupting T-cell activation and proliferation.



    • Due to their potent and immediate immunosuppressive effects, induction agents allow for CNI therapy to be postponed in the setting of delayed graft function.


    • These same agents may also be used to treat acute rejection


  • There are four types of agents used for induction therapy or the treatment of acute rejection:



    • Polyclonal antibodies


    • Monoclonal antibodies


    • Interleukin-2 (IL-2) receptor antibodies


    • High-dose glucocorticoids


  • Polyclonal antibodies



    • Polyclonal antibodies are produced by immunizing animals such as rabbits (rabbit antithymocyte globulin [rATG]; Thymoglobulin; rabbit ATG-Fresenius) or horses (Atgam)17,18,19 with human lymphoid cells.22


    • General mechanism of action



      • Polyclonal antilymphocyte globulins are a group of antibodies targeting multiple antigens (CD2, CD3, CD4, CD8, CD11a, and CD18) on the cell membrane of lymphocytes (hence the name “polyclonal”)


      • These antithymocyte antibodies bind to lymphocytes that display the specific surface antigen and deplete lymphocytes from the circulation for several weeks. This helps to prevent early posttransplant ischemia-reperfusion injury.



      • In addition, rabbit antithymoglobulin (rATG) has been shown to prevent B-cell proliferation and differentiation, which decreases circulating antibodies and promotes antibody-dependence cell-mediated cytotoxicity.


      • This lymphopenia is the basis for the immunosuppressive action of polyclonal antibodies.


    • Use in transplantation



      • In the United States, rATG and Atgam are approved by the Food and Drug Administration (FDA) for the treatment of acute rejection in kidney transplant recipients.


      • Both rATG and Atgam are also used off-label as induction therapy agents in nonrenal solid organ transplantation.


      • When given intraoperatively, prior to reperfusion, rATG has been shown to reduce the incidence of delayed graft function in both kidney and heart transplant recipients.


    • Specific polyclonal antibody agents:



      • Antithymocyte globulin—Rabbit (rATG, Thymoglobulin)



        • Dosage and administration—Induction therapy



          • Dose used in clinical trials is usually 1.5 mg/kg/day for 3 to 7 days.


        • Dosage and administration—Treatment of acute rejection



          • Recommended dose: 1.5 mg/kg/day for 7 to 10 days


      • ATG-Fresenius



        • Dosage and administration—Induction therapy



          • Dose ranges from 2 to 5 mg/kg body weight given as an infusion over 4 hours. Duration of therapy may last 5 to 14 days.


          • Single shot infusion over 4 hours (4 to 6 mg/kg body weight) for one dose prior to initiation of standard immunosuppression and administration.


        • Dosage and administration—AMR therapy



          • Dose ranges from 3 to 5 mg/kg body weight given as an infusion over 4 hours. Duration of therapy may last 5 to 14 days.


      • Lymphocyte immune globulin—Equine (Atgam)



        • Dosage and administration—Induction or AMR therapy



          • Doses range from 10 to 15 mg/kg given over a 4-hour infusion for up to 14 days.


          • Intradermal skin test Instructions for Atgam: 0.1 mL of 1:1,000 dilution (5 µg horse IgG) in 0.9% sodium chloride injected intradermally with a contralateral 0.9% sodium chloride control injection. Monitor patient and skin test area every 15 to 20 minutes for 1 hour. A positive skin test result consists of a local reaction equal to 10 mm with erythema and/or wheal or marked local swelling.


        • The following precautions are recommended to prevent infusion-related adverse effects for all polyclonal antibody agents:



          • Patients receive premedication with corticosteroids, acetaminophen, and an antihistamine 30 to 60 minutes prior to the infusion, this is typically used prior to the first three doses (regardless if used for induction or AMR therapy or the length of treatment).


          • Always administered through a high-flow vein.



          • The first dose should be infused over at least 6 hours and subsequent doses should be infused over at least 4 hours. This process should be followed with every course of therapy regardless if used as induction or AMR treatment.


          • Assess for anaphylaxis during first three doses as those are the highest risk for adverse effects.


        • Consider dose reduction in setting of



          • Platelet count between 50,000 and 75,000 cells/mm3


          • White cell count between 2,000 and 3,000 cells/mm3


          • Consider discontinuing treatment in the setting of



            • Persistent and severe thrombocytopenia (<50,000 cells/mm3)


            • Leukopenia (<2,000 cells/mm3)


        • Drug interactions



          • No formal drug-drug interactions have been reported to date


        • Adverse effects of polyclonal antibodies



          • The most common side effects are infusion-related (fever, chills, headache), leukopenia, and thrombocytopenia.


          • Other side effects include serum sickness, hypertension, tachycardia, dyspnea, abdominal pain, myalgias, and diarrhea.


        • Serious immune-mediated reactions have been reported with the use of polyclonal antibodies ranging from a systemic rash, serum sickness to anaphylaxis with tachycardia, dyspnea, hypotension, or death. The infusion should be immediately stopped and the physician should be notified.


        • Some programs have an emergency anaphylaxis kit available for use if suspected anaphylactic reactions occur. These kits may contain the following:



          • Epinephrine 1:1,000, 3 vials (0.5 mg SQ)


          • Solucortef 100 mg IV (to be given over 30 seconds)


          • Diphenhydramine 50 mg IV (give 25 mg over 1 minute)


          • Albuterol inhaler (give 2 puffs for anaphylaxis)


          • Prefilled saline syringes


          • Ambu bag, face mask and oral airway


        • Anytime polyclonal therapy is used, the patient may need to be treated with anti-infective prophylaxis (refer to your program protocols) including:



          • Nystatin swish and swallow 5 mL po or clotrimazole (Mycelex) troche 10 mg QID for antifungal prophylaxis


          • Acyclovir (Zovirax) 400 mg po every 12 hours (if CMV, low-risk category)


          • Valganciclovir (Valcyte) 900 mg po daily (if CMV, moderate or high risk)


          • Trimethoprim/sulfamethoxazole (Bactrim) double strength, 1 tablet once daily, three times a week or weekly depending on your center protocol for pneumocystis prevention.


  • Monoclonal antibodies: alemtuzumab (Campath-1H)



    • There have been several monoclonal antibodies developed for use in transplantation over the last two decades. Many of these antibodies have been subsequently withdrawn from the worldwide market.



    • Alemtuzumab (Campath-1H)



      • Alemtuzumab is a humanized monoclonal antibody directed against the CD52 receptor and used for induction therapy in solid organ transplantation.5



        • Alemtuzumab is FDA approved only for treating refractory B-cell chronic lymphocytic leukemia and multiple sclerosis and is used off-label for induction therapy in solid organ transplantation by a limited number of transplant centers.


        • Studies in kidney transplant recipients have shown that use of alemtuzumab as induction therapy was superior to rATG and conventional immunosuppression for the prevention of rejection in the first year.5,6


      • Alemtuzumab—Dosing and administration



        • Give alemtuzumab 30 mg intravenously (IV) or subcutaneously (SC) once at the time of transplantation


        • Must premedicate with a minimum of methylprednisolone 250 mg IV to avoid immunoactivation and immune-mediated infusion reactions


        • Infusion-related side effects of alemtuzumab are common including fever, chills, hypertension, and hypotension. These side effects are reduced when alemtuzumab is administered SC.


      • Alemtuzumab—Adverse effects:



        • The side effects of alemtuzumab in solid organ transplant patients are different than the side effects in oncology patients because of the differences in dosage used.


        • Lymphopenia is the basis of alemtuzumab’s immunosuppressive action.


        • Therefore, patients receiving alemtuzumab are at increased risk of opportunistic infections, autoimmune disorders, and profound pancytopenia


      • Alemtuzumab—Black box warning



        • Alemtuzumab carries a black box warning stating increased risk of severe hematologic toxicities, infusion reactions, infection, and opportunistic infections.


        • Alemtuzumab—Therapeutic drug monitoring



          • Complete blood counts and platelet counts should be monitored routinely.


  • Interleukin-2 (IL-2) receptor antibodies: Basiliximab (Simulect)22



    • A nondepleting monoclonal antibody that serves as an interleukin-2 (IL-2) receptor antagonist.


    • Currently approved as induction therapy to prevent rejection in patients who have a low-to-moderate risk of rejection.


    • Also a chimeric (murine/human) monoclonal antibody that contains more mouse than human proteins; produced by recombinant DNA technology.


    • Basiliximab—Mechanism of action



      • Binds to the alpha subunit of the IL-2 receptor expressed only on activated T cells to inhibit their proliferation without destroying the lymphocyte.


    • Basiliximab—Dosing and administration



      • 20 mg given IV over 15 to 30 minutes or IV push on day 0 and day 4 posttransplant.



    • Basiliximab—Drug interactions



      • No formal drug-drug interactions have been reported to date.


    • Basiliximab—Adverse effects



      • Basiliximab is well tolerated.


      • Occasionally infusion-related side effects such as fever and chills have been reported.


    • Basiliximab—Therapeutic drug monitoring.



      • Currently, routine therapeutic monitoring of basiliximab is not indicated.


  • Glucocorticoids in high dose: Methylprednisolone (Solu-Medrol); prednisone



    • Discussed under maintenance immunosuppression below


III. MAINTENANCE IMMUNOSUPPRESSION THERAPY

A. Goal



  • The primary goal of immunosuppressive therapy in solid organ transplantation is to maintain graft tolerance using the least amount of drugs possible.


  • Triple immunosuppression allows adequate treatment combining three drugs in lower doses to minimize side effects, reduce the risk of allograft rejection or graft dysfunction, and prevent long-term complications such as infection, chronic kidney disease, cancer, or other comorbidities.24,25,26,27,28,29,30


  • Currently, the combination of tacrolimus (often referred to as “TAC”), mycophenolate mofetil (MMF), and a corticosteroid is the most frequently used triple immunosuppression regimen for solid organ transplant recipients in the United States across all organ systems.24,25,26,27,28,29,30

B. Calcineurin inhibitors31,32,33,34,35,36,37,38,39,40,41,42



  • Quickly became the standard for primary immunosuppression through selective immunosuppressive actions which have dramatically decreased the incidence of acute cellular rejection with minimal toxicities to the bone marrow.


  • The decision on the initial dose and the time to initiate CNIs is dependent on



    • Initial allograft function.


    • Other medical conditions (e.g., presence of active infection or impaired renal function).


    • Use of concurrent immunosuppressive agents.


    • Subsequently, the dose of CNI is adjusted to achieve target trough blood concentrations.


  • Types of CNIs:



    • Cyclosporine


    • Tacrolimus


  • Cyclosporine31,32,33,35,36,37



    • Overview



      • First CNI used in transplantation.


      • Introduced in the early 1980s and revolutionized transplant medicine by transforming organ transplantation from an experimental procedure into routine clinical practice.


    • There are two formulations of cyclosporine:



      • Nonmodified (Sandimmune).


      • Modified, as microemulsion (Neoral, Gengraf).


      • There are generic equivalents for both formulations of cyclosporine.


      • Most importantly, these formulations are not easily interchangeable.


    • Cyclosporine—Mechanism of action.37




      • CNIs primarily suppress the activation of T lymphocytes and inhibit intracellular gene transcription in the production of the lymphokine IL-2. IL-2 is essential for activation and proliferation of T cells in response to alloantigens.


      • Cyclosporine



        • Inhibits calcineurin by binding to an intracellular protein cyclophilin.


        • Reversibly inhibits production of lymphokines such as IL-2 in immunocompetent lymphocytes. This leads to preferential inhibition of T lymphocytes.


    • Cyclosporine—Dosing and administration32,33,37



      • Recommended starting oral dose in following recipients:



        • Kidney: 3 mg/kg/day in 2 divided doses


        • Liver: 4 mg/kg/day in 2 divided doses


        • Heart: 3 mg/kg/day in 2 divided doses


        • Lung: no dosing recommendations, is used off-label as there are no immunosuppressive medications with FDA approval for lung transplantation.30


      • The IV dose is usually one-third the oral dose and is administered as a continuous infusion, or as an intermittent bolus twice daily with a 4- to 6-hour infusion time per dose.37


    • Cyclosporine—Therapeutic drug monitoring



      • The reported therapeutic range for 12-hour trough levels appears to be between 100 and 400 ng/mL.33


      • Trough targets are program, patient, agent, and regimen specific. Generally, the cyclosporine trough target will be highest within the first 6 posttransplant months, tapering to lower target maintenance troughs after 6 to 12 months, depending on rejection pathology.


    • Cyclosporine—Drug interactions (Table 41-2)37,38,39,40,41








      TABLE 4-2 Drugs that Commonly Interact with Cyclosporine (CsA) and Tacrolimus (TAC)












































      Increases CsA or TAC Concentrations

      Decreases CsA or TAC Concentrations


      Antifungal agents

      Antibiotics

      Clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole


      Nafcillin, rifabutin, rifampin


      Calcium channel blockers

      Antiepileptic agents

      diltiazem, nicardipine, nifedipine, verapamil


      carbamazepine, phenobarbital, phenytoin


      Macrolide antibiotics

      Others

      clarithromycin, erythromycin


      St. John’s wort, octreotide, orlistat, coadministration of electrolytes (potassium/magnesium)


      HMG-CoA reductase inhibitors

      simvastatin, lovastatin



      Others

      bromocriptine, danazol, fluvoxamine, grapefruit juice, protease inhibitors


      Neoral® [Package Insert]. East Hanover, NJ: Novartis Pharmaceutical Corp.; March 2015. Available at https://www.pharma.us.novartis.com/product/pi/pdf/neoral.pdf. Accessed October 17, 2015; Issa N, Kukla A, Ibrahim HN. Calcineurin inhibitor toxicity: a review and perspective of the evidence. Am J Nephrol. 2013;37(6):602-612; Castrogudin JF, Molina E, Vara E. Calcineurin inhibitors in liver transplantation: to be or not to be. Transplant Proc. 2011;43(6):2220-2223; Prograf® [Package Insert]. Deerfield, IL: Astellas Pharma U.S., Inc.; May 2015. Available at https://www.astellas.us/docs/prograf.pdf. Accessed October 17, 2015; Patel JK, Kobashigawa JA. Tacrolimus in heart transplant recipients: an overview. BioDrugs. 2007;21(3):139-143.





      • Any drugs that either inhibit or induce cytochrome P-450 3A4 will alter the metabolism of cyclosporine:



        • Drugs that inhibit cyclosporine metabolism can lead to higher drug levels and increase the risk for toxicity.


        • Drugs that induce cyclosporine metabolism can lead to subtherapeutic cyclosporine drug levels and increase the risk of rejection.


      • A list of drugs that commonly interact with cyclosporine and tacrolimus is provided in Table 4-237,38,39,40,41



        • Please note that this list is not comprehensive.


        • Drugs that are nephrotoxic such as IV tobramycin and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen may potentiate the nephrotoxic effects of CNI.



          • Concurrent administration of these agents should be avoided unless no other therapeutic options exist.


    • Cyclosporine—Adverse effects



      • The most common side effects of cyclosporine are as follows37,38,39,40,41:



        • Hypertension.


        • Dyslipidemia.


        • Cosmetic (hirsutism, gingival hyperplasia).


        • Nephrotoxicity.


        • Diabetes mellitus (DM).


        • Tremor.


        • Rare: seizures, posterior reversible encephalopathy syndrome, hallucination, and migraine.


        • As with all immunosuppressive agents, long-term use of cyclosporine is associated with an increased risk of opportunistic infection and malignancy.


  • Tacrolimus (Prograf, Hecoria, Astagraf)40,41,42,43,44



    • Overview



      • A macrolide lactone antibiotic isolated from the fungus Streptomyces tsukubaensis.


      • Introduced in 1994


      • Differs structurally from cyclosporine; more potent than cyclosporine


      • Used in solid organ transplantation as part of dual or triple immunosuppressive maintenance regimens to prevent allograft rejection


      • Initiated at the time of transplantation and usually continued for the life of the allograft


      • Most frequently used CNI


    • Tacrolimus—Mechanism of action40



      • Tacrolimus inhibits calcineurin by binding to the intracellular cytosolic protein called FKBP-12 (FK-binding protein).


      • Prevents gene transcription and the formation of lymphokines such as IL-2 and gamma interferon.


      • The net effect is inhibition of T-cell activation resulting in immunosuppression.


    • Tacrolimus—Dosing and administration25,29,33,34,40




      • Recommended weight-based starting oral dose in following types of transplant recipients:



        • Adult kidney: 0.2 mg/kg/day in 2 divided doses


        • Adult liver: 0.10 to 0.15 mg/kg/day in 2 divided doses


        • Adult heart: 0.075 mg/kg/day in 2 divided doses


        • Pediatric liver: 0.15 to 0.20 mg/kg/day in 2 divided doses.


      • Fixed-dose starting oral dose:



        • All organs: start around 2 mg/day in divided doses titrating (increasing or decreasing) the dose by 1 to 2 mg/day to achieve target trough


        • The typical IV dose is 0.03 to 0.05 mg/kg/day as a continuous infusion. Similar to cyclosporine, the typical infusion dose is 1/3 to 1/5 of the oral dose per day delivered as a continuous infusion.


    • Tacrolimus—Therapeutic drug monitoring25,29,33,34,40



      • Reported therapeutic tacrolimus range for 12-hour trough levels from whole blood typically ranges between 5 and 20 ng/mL.


      • Trough targets are organ, time posttransplant, patient, agent, and program specific. Generally, the trough target will be highest within the first 6 posttransplant months, tapering to lower target maintenance troughs after 6 to 12 months depending on rejection pathology.


      • The target therapeutic range for CNIs varies depending on



        • Type of organ transplanted.


        • Functional status of the allograft.


        • Medical conditions of the patient. (e.g., presence of active infection or impaired renal function)


        • Concurrent immunosuppressive agents used.


    • Tacrolimus: Drug interactions (see Table 4-2)37,38,39,40,41



      • Any drugs that either inhibit or induce cytochrome P-450 3A4 will alter the metabolism of tacrolimus.



        • Drugs that inhibit tacrolimus metabolism can lead to higher drug levels and increase the risk for toxicity.


        • Drugs that induce tacrolimus metabolism can lead to subtherapeutic tacrolimus drug levels and increase the risk of rejection.21,22


      • A list of the drugs that commonly interact with cyclosporine and tacrolimus is provided in Table 4-2.37,38,39,40,41


    • Tacrolimus—Adverse effects

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Oct 27, 2018 | Posted by in NURSING | Comments Off on Transplant Pharmacology

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