Immunosuppression for Solid Organ Transplantation: A Focused Medication Review

Lindsay A. Helms, PharmD, BCPS*
Clinical Specialist, Surgical Critical Care
The Johns Hopkins Hospital
Baltimore, Maryland, USA

Kathryn A. Connor, PharmD, BCPS, BCNSP**
Assistant Professor
St. John Fisher College of Pharmacy
Clinical Specialist
University of Rochester Medical Center
Rochester, New York, USA

Without pharmacologic intervention, it would be virtually impossible to perform solid organ transplantations successfully. The first such procedure was conducted in 1964 on identical twins; unfortunately, as similar attempts progressed, it became clear that not all patients are created equal -- not even identical twins. To prevent acute rejection of transplanted organs, researchers experimented with therapies such as full-body irradiation; others worked hard to formulate and refine agents
used for immunosuppression. In this focused medication review, the continuum of immunosuppressive agents and regimens utilized for induction, maintenance and acute rejection therapy for solid organ transplantation are discussed.

Cyclosporine A and tacrolimus. These agents inhibit T-cell activation and proliferation by stopping interleukin (IL)- 2 gene transcription.(1) Tacrolimus (formerly FK-506) is approximately 100 times more potent than cyclosporine.(1) Serum concentrations of cyclosporine and tacrolimus must be monitored by checking trough levels. The goal level may vary depending on the organ type and the time from transplantation. Calcineurin inhibitors are a mainstay in immunosuppressive regimens, but using these agents does not come without risk. Neuro- and nephrotoxicity are adverse reactions frequently seen, and sequelae may hinder a patient from actually achieving and maintaining therapeutic levels. Other adverse effects associated with these calcineurin inhibitors include hypertension, hyperlipidemia, diabetes, hyperkalemia and metabolic acidosis.(1) Cyclosporine is available in two oral formulations – Neoral® and Sandimmune® (Novartis; Basel, Switzerland) – and an intravenous formulation. Tacrolimus is available as an oral capsule, which can be used to compound into a suspension or as a highly potent intravenous formulation, which many providers avoid because of increased risk of nephrotoxicity.

Azathioprine. An anti-metabolite, this agent was the first immunosuppressive drug available. It is a pro-drug that is converted to 6-mercaptopurine, and then further metabolized and incorporated into DNA, ultimately halting replication.(2) It is not used for immunosupression frequently because of its lack of potency compared to newer anti-metabolite agents, such as mycophenolate, but it can be beneficial in anti-hepatitis C virus activity.(3.4)

Mycophenolic acid. Marketed as mycophenolate mofetil (CellCept®; Roche, New Jersey, USA) and mycophenolate sodium (Myfortic®; Novartis, Basel, Switzerland), these have been used since the 1990s as adjunct immunosuppressive agents after solid organ transplant. They inhibit enzymatic production of inosine 5’ monophosphate dehydrogenase, preventing synthesis of guanosine-nucleoside and blocking the proliferation of lymphocytes.(1) Mycophenolate mofetil’s tendency to cause high rates of gastrointestinal upset is often a dose-limiting side effect. Mycophenolate sodium was created as a slow-release formulation in hopes of decreasing this adverse effect. Unfortunately, no significant difference between the formulations has been recorded.(3) Both may cause profound myelosuppression that can lead to increased risk of fungal and viral infections. Mycophenolate mofetil is available in oral and intravenous formulations.

Polyclonal Antibodies. This technique is used to delay time to exposure of toxic immunosuppressants, such as calcineurin inhibitors, and to prevent hyperacute rejection in highly sensitized patients. Polyclonal antibody formulations (antithymocyte globulins [ATG] and anti-lymphocyte globulins [ALS]), created by inoculating rabbits or horses with human lymphocytes or thymocytes, primarily are used as induction therapy agents intraoperatively. They are continued for a short time immediately after transplantation. This therapy also can be utilized for acute rejection. Polyclonal antibodies are thought to deplete alloreactive lymphocytes through complement mediated cell lysis and uptake into the reticuloendothelial system, which allows the immune system to reset and recognize the foreign organ as self.(4) The most common reaction associated with thymoglobulin administration is fever; however, these formulations also may cause allergic reaction, pancytopenia and serum sickness with repeated exposure.(1,4)

Corticosteroid therapy. Used for induction, maintenance therapy and in the treatment of acute rejection, these agents inhibit arachidonic acid metabolism and IL-1-dependent lymphocyte activation. Steroids mitigate the inflammatory process and also may affect antigen presentation on the dendritic cells.(3) It is hypothesized that steroid therapy also may cause the sequestration of lymphocytes and monocytes in the lymph nodes and lymphoid organs.(2) Because of side effects – including hypertension, hyperglycemia and osteoporosis – many institutions are evaluating the role of steroid minimization protocols. However, research already has shown that early discontinuation of steroids (one week post-transplant) leads to increased incidence and severity of rejection.(4) If there is no sign of rejection, steroid doses may be titrated gradually and stopped after three to six months.(2) Steroids usually are administered intravenously during induction therapy, perioperatively and for the treatment of acute rejection; they are then given orally for maintenance therapy.

Sirolimus. A potent immunosuppressive agent, sirolimus (Rapamune®; Wyeth, Philadelphia, Pennsylvania, USA ) was approved in 1999 for prophylaxis against organ rejection in patients undergoing renal transplantation.(5) It is a macrolide antibiotic produced by Streptomyces hygroscopicus, originally developed as an antifungal agent. Structurally, sirolimus is similar to tacrolimus; it binds to the same target FK-binding protein, but with higher affinity than tacrolimus. Sirolimus does not inhibit calcineurin like tacrolimus, despite its similar sounding name. Sirolimus works by blocking the transduction signal from the IL-2 receptor, thereby inhibiting T-cell and B-cell proliferation. This different mechanism of action provides for the major advantage of sirolimus over calcineurin inhibitors: lack of inherent nephro- and neurotoxicity. Just like tacrolimus, careful therapeutic drug level monitoring is required to optimize therapy.

The Food and Drug Administration (FDA) issued an alert in June 2009 after the results of a clinical trial conducted by the manufacturer suggested increased mortality rates in liver transplant patients after converting from a calcineurin inhibitor-based regimen to sirolimus.(6,7) The FDA is reviewing these data and will make recommendations as appropriate. In the interim, healthcare professionals are advised to use sirolimus according to its labeling and to report adverse events to the FDA Safety Information and Adverse Event Reporting program. Because of sirolimus’s profound deleterious effects on the healing process, many practitioners avoid early postoperative administration to allow adequate time for healing.

Muromonab-CD3. This agent (Orthoclone OKT®3; Ortho Biotech, Raritan, New Jersey) targets CD3 molecules on T cells, which leads to T-cell lysis and profound lymphodepletion within minutes of administration.(4) Muromonab-CD3 must be administered with steroids to decrease the reaction associated with the massive cytokine release caused by this preparation.(4) The primary use for muromonab-CD3 is treatment of acute rejection, specifically steroid-resistant rejection.4

Basiliximab and Daclizumab. Basiliximab (Simulect®; Novartis, Basel, Switzerland) and daclizumab (Zenapax®; Roche, Nutley, New Jersey, USA) are humanized monoclonal antibodies against the IL-2 receptor and prevent activation of lymphocytes, which impairs the response of the immune system to antigens. They are both approved to decrease acute organ rejection in renal transplantation. Their chimeric structure makes them less immunogenic than muromonab- CD3; they also have longer half-lives and are better tolerated. Basiliximab and daclizumab are given during the immediate peri-transplant period and at specific times post-transplant. The patient and medical team should be vigilant about giving premedication and monitoring hypersensitive reactions. Both agents are similar clinically, but their efficacy has not been compared directly in clinical trials. The decision to use one agent preferentially may be largely based on cost and ease of administration. Supply of daclizumab is limited, as the manufacturer stopped production in late 2009.

Alemtuzumab. A humanized monoclonal antibody approved for the treatment of B-cell chronic lymphocytic leukemia, (MabCampath®; Bayer Schering Pharma AG, Berlin, Germany), alemtuzumab also is being investigated for the treatment of acute rejection in transplantation. Alemtuzumab works by binding to CD52, a non-modulating antigen present on the surface of B and T lymphocytes, resulting in an antibody-dependent lysis of leukemic cells. Data on the use of alemtuzumab in the treatment of acute rejection is limited, and the optimal dosing regimen is unclear. As its role is elucidated further, clinicians should be aware that appropriate infection prophylaxis with this agent is crucial, as alemtuzumab therapy comes with an increased risk for opportunistic infections, particularly reactivation of cytomegalovirus.

Belatacept. Costimulatory blockade has long been recognized as an important target for immunomodulation in solid organ transplantation. Belatacept (LEA29Y), a selective blocker of T-cell activation, is an investigational fusion protein under development.(8) It is the first in a new class of immunosuppressive agents intended to provide extended graft survival, while limiting the toxicity generated by standard immune-suppressing regimens, such as calcineurin inhibitors and steroid-based treatments. This agent works best when combined with therapies that target different pathways of T-cell activation. Phase III trials are underway; results may help determine the most effective regimen for this new immunosuppressive therapy.(9)

Efalizumab. Efalizumab (Raptiva®; Merck Serono, Geneva, Switzerland) is a recombinant monoclonal antibody that binds to CD11a subunit of lymphocyte function-associated antigen-1 (LFA-1), a leukocyte surface protein, blocking multiple T cell- mediated responses. Efalizumab was approved for use in psoriasis and had been studied as an immunosuppressive agent in organ transplantation. This agent was removed from the market in April 2009 because of an associated increased risk of progressive multifocal leukoencephalopathy.(10)

Everolimus. This agent (Afinitor®; Novartis, Basel, Switzerland) was approved by the FDA in March 2009 for advanced renal cell carcinoma. Investigation of use in transplant patients now is underway within the United States, but under the name Certican® (Novartis, Basel, Switzerland), it has been used in other countries to prevent acute rejection in kidney and heart transplant. Everolimus is a structural analogue of sirolimus with a similar mechanism of action, a shorter half-life and increased bioavailability.(11) It may be utilized in heart transplantation and a play a role similar to that of sirolimus in kidney and other transplants.

Approaches to immunosuppression with solid organ transplantation vary. Many regimens are tailored to the patient and individual tolerance – or intolerance – of these agents. Ongoing research is needed to find the ideal immunosuppressive agent and the ideal regimen. The advances of the last decade have made organ transplantation more successful across the patient spectrum, from the high-risk, highly sensitized to the ideal, ABO- and antibody-matched patient.

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