Induction Immunosuppressive Therapies in Renal Transplantation

Steven Gabardi, Pharm.D., BCPS; Spencer T. Martin, Pharm.D., BCPS; Keri L. Roberts, Pharm.D.; Monica Grafals, M.D.

Disclosures

Am J Health Syst Pharm. 2011;68(3):211-218. 

In This Article

Nondepleting Agents

Basiliximab

Pharmacology. Basiliximab binds with high affinity to the alpha subunit of the IL-2 receptor, also known as CD25, where it acts as a receptor antagonist. The antagonistic effect on the IL-2 receptor prevents T-cell activation and subsequent proliferation without causing lysis or cell destruction.[10,19] Basiliximab is considered a chimeric antibody, because it consists of approximately 70% human and 30% murine proteins.[10,19,44] This agent has low immunogenicity potential due to the incorporation of human protein sequences.

Dosage. Basiliximab is labeled for induction therapy in renal transplant recipients.[19] The approved dose of basiliximab is 20 mg i.v. given two hours before renal transplantation, followed by a second 20-mg dose on posttransplantation day 4.[11,19] This dosing schedule can be used for both adults and children weighing at least 35 kg. These doses should be decreased to 10 mg for patients weighing less than 35 kg.[11,19] After administration, basiliximab causes a complete saturation of the CD25 receptor for five to eight weeks.[10,11]

Adverse Effects. Safety is one of the most evident benefits of induction therapy with an IL-2 receptor antibody, especially the absence of any increased risk of CMV infection or malignancy. In clinical trials, the frequency of all adverse reactions with basiliximab was similar to that seen with placebo.[10,11,19]

Hypersensitivity reactions are considered the most serious adverse effects associated with the use of basiliximab but occur infrequently (<1%) during initial and subsequent dosing administration.[10,11,19] Such an event is multifaceted and similar to previously mentioned hypersensitivity episodes. The most serious adverse effects of a hypersensitivity reaction include hypotension, tachycardia, cardiac failure, bron-chospasms, pulmonary edema, and respiratory failure.[19]

Another possible advantage of basiliximab is its apparent low risk of malignancy versus that of the antithymocyte globulins.[10,11,19] This is difficult to fully elucidate, as few head-to-head studies of these agents have been completed. For those studies that are available, the evaluation period was often 12 months or less.

Clinical Efficacy. Lebranchu et al.[45] conducted the first comparison of basiliximab and antithymocyte globulin (rabbit) for induction therapy in an open-label, randomized, multicenter study over six months. The patients included in the trial (treated with basiliximab [n = 51] or antithymocyte globulin [rabbit] [n = 50]) were receiving a renal transplant from a deceased donor. Basiliximab 20 mg was administered within 2 hours of surgery and again on posttransplantation day 4. Antithymocyte globulin (rabbit) 1.0–1.5 mg/kg/day was given for 6–10 days, with the initial dose administered within 24 hours pretransplantation. All patients received cyclosporine microemulsion, mycophenolate mofetil, and corticosteroids. Efficacy endpoints, including patient survival, graft survival, episodes of BPAR, and treatment failure, were similar between groups. From a tolerability standpoint, antithymocyte globulin (rabbit) resulted in an increased rate of fever, gastric disorders, leukopenia, anemia, hepatitis, and serum sickness compared with basiliximab. Basiliximab had an increased frequency of central nervous system and urinary disorders. CMV infection occurred more frequently in the group treated with antithymocyte globulin (rabbit). A pharmacoeconomic analysis of this study determined that regardless of basiliximab's higher overall cost of administration, its medical cost savings resulted in an increased cost-effectiveness of $1459 per patient (in 2004 U.S. dollars).[46]

Mourad et al.[47] conducted an open-label multicenter trial in which 105 transplant recipients were randomized to receive antithymocyte globulin (rabbit) (n = 53) or basiliximab (n = 52). Patients were eligible regardless of whether they were receiving their first or second transplant from a deceased donor and were given a maintenance regimen consisting of cyclosporine microemulsion, mycophenolate mofetil, and corticosteroids. BPAR, patient and graft survival, and treatment failure occurred at almost identical rates. As in other studies, antithymocyte globulin (rabbit) use resulted in significantly higher rates of serum sickness, leukopenia (p = 0.0007), thrombocytopenia (p < 0.0001), and CMV disease (p = 0.025) versus basiliximab.

Brennan et al.[48] conducted a comparative prospective, randomized trial to assess the composite endpoint of BPAR, delayed graft function, graft loss, and patient death at 12 months posttransplantation. Patients were required to have at least one risk factor that would categorize them as high risk for acute rejection or delayed graft functioning (i.e., cold-ischemic time exceeding 24 hours, donor age of >50 years, donor serum creatinine concentration of >2.5 mg/dL, or donor without a heartbeat). Antithymocyte globulin (rabbit) was dosed at 1.5 mg/kg, with the initial dose administered intraoperatively and once everyday thereafter until a total dose of 7.5 mg/kg had been achieved (n = 141). A 20-mg dose of basiliximab was administered before graft reperfusion and on postoperative day 4 (n = 137). Maintenance therapy included mycophenolate mofetil 1000 mg twice daily, prednisone 5 mg/day by six months, and cyclosporine microemulsion. The composite endpoint did not differ significantly between the antithymocyte globulin [rabbit] group and the basiliximab-treated group (50.4% versus 56.2%, respectively; p = 0.34). However, BPAR alone occurred more frequently in the basiliximab-treated group (25.5% versus 15.6% with antithymocyte globulin [rabbit]) (p = 0.02), while antithymocyte globulin (rabbit) was associated with a higher overall infection rate (85.8% versus 75.2%, p = 0.03). Surprisingly, basiliximab was associated with an increased rate of CMV infection (17.5% versus 7.8% with antithymocyte globulin [rabbit]) (p = 0.02). Leukopenia was again found to be more prevalent among patients treated with antithymocyte globulin (rabbit).

Daclizumab

Much like basiliximab, daclizumab is a nondepleting monoclonal antibody that acts as an antagonist at the CD25 subunit of T cells and received marketing approval in 1997 for induction therapy in renal transplant recipients.[49] Daclizumab consists of 90% human and 10% murine components. The effectiveness of daclizumab is comparable to that of basiliximab, with an adverse-effect profile comparable to that seen with placebo. The major difference between daclizumab and basiliximab is that daclizumab has a more complicated, lengthy, and potentially more costly dosing regimen. In 2009, the manufacturer of daclizumab announced that it would no longer produce the agent due to high production costs and a lack of demand. Daclizumab supplies are expected to last through 2010. Once these supplies have been exhausted, daclizumab will no longer be available for clinical use. Thus, the use of daclizumab in clinical practice is not discussed herein.

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