Drugs

, Volume 63, Issue 24, pp 2803–2835

Basiliximab

A Review of its Use as Induction Therapy in Renal Transplantation
Adis Drug Evaluation

DOI: 10.2165/00003495-200363240-00009

Cite this article as:
Chapman, T.M. & Keating, G.M. Drugs (2003) 63: 2803. doi:10.2165/00003495-200363240-00009
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Summary

Abstract

Basiliximab (Simulect®), a chimeric (human/murine) monoclonal antibody, is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents.

Basiliximab significantly reduced acute rejection compared with placebo in renal transplant recipients receiving dual-(cyclosporin microemulsion and corticosteroids) or triple-immunotherapy (azathioprine- or mycophenolate mofetil-based); graft and patient survival rates at 12 months were similar. Significantly more basiliximab than placebo recipients were free from the combined endpoint of death, graft loss or acute rejection 3 years, but not 5 years, after transplantation.

The incidence of adverse events was similar in basiliximab and placebo recipients, with no increase in the incidence of infection, including cytome-galovirus (CMV) infection. Malignancies or post-transplant lymphoproliferative disorders after treatment with basiliximab were rare, with a similar incidence to that seen with placebo at 12 months or 5 years post-transplantation. Rare cases of hypersensitivity reactions to basiliximab have been reported.

The efficacy of basiliximab was similar to that of equine antithymocyte globulin (ATG) and daclizumab, and similar to or greater than that of muromonab CD3. Basiliximab was as effective as rabbit antithymocyte globulin (RATG) in patients at relatively low risk of acute rejection, but less effective in high-risk patients. Numerically or significantly fewer patients receiving basiliximab experienced adverse events considered to be related to the study drug than ATG or RATG recipients. The incidence of infection, including CMV infection, was similar with basiliximab and ATG or RATG.

Basiliximab plus baseline immunosuppression resulted in no significant differences in acute rejection rates compared with baseline immunosuppression with or without ATG or antilymphocyte globulin in retrospective analyses conducted for small numbers of paediatric patients. Limited data from paediatric renal transplant recipients suggest a similar tolerability profile to that in adults.

Basiliximab appears to allow the withdrawal of corticosteroids or the use of corticosteroid-free or calcineurin inhibitor-sparing regimens in renal transplant recipients.

Basiliximab did not increase the overall costs of therapy in pharmacoeconomic studies.

Conclusion: Basiliximab reduces acute rejection without increasing the incidence of adverse events, including infection and malignancy, in renal transplant recipients when combined with standard dual- or triple-immunotherapy. The overall incidence of death, graft loss or acute rejection was significantly reduced at 3 years; there was no significant difference for this endpoint 5 years after transplantation. Malignancy was not increased at 5 years. The overall efficacy, tolerability, ease of administration and cost effectiveness of basiliximab make it an attractive option for the prophylaxis of acute renal transplant rejection.

Pharmacodynamic Properties

Basiliximab is a chimeric (human/murine) monoclonal antibody with specificity and high affinity for the α subunit of the interleukin (IL)-2 receptor (IL-2Rα) on the surface of activated T lymphocytes.

Basiliximab acts as an IL-2Rα antagonist and inhibits IL-2-mediated activation and proliferation of T lymphocytes. The binding of basiliximab to IL-2Rα also has an effect on peripheral blood mononuclear cell proliferation mediated by IL-15.

Serum concentrations >0.2 μg/mL are sufficient to saturate IL-2Rα on circulating T lymphocytes. The mean duration of IL-2Rα saturation in adult renal transplant recipients receiving basiliximab 20mg on days 0 and 4 was 36–49 days. The duration of IL-2Rα saturation is extended in the presence of azathioprine or mycophenolate mofetil (MMF). The mean duration of IL-2Rα saturation in paediatric patients was 31–42 days for those receiving basiliximab 10 (bodyweight <40kg) or 20 mg/dose (bodyweight >40kg), or 12 mg/m2.

Treatment with basiliximab significantly reduced the number of circulating T lymphocytes expressing IL-2Rα, but the numbers of total lymphocytes, lymphocyte subtypes or T lymphocytes expressing activation antigens other than IL-2Rα were unaffected.

Basiliximab was minimally immunogenic; the incidence of an anti-idiotype antibody response in renal transplantation recipients treated with basiliximab was 4 in 339 patients and did not appear to be clinically significant. Human antimurine antibody responses were reported in 2 of 138 renal transplant recipients treated with basiliximab but not exposed to muromonab CD3, and in 4 of 34 patients who received basiliximab and muromonab CD3 concomitantly, suggesting the high antibody response is due to muromonab CD3.

Pharmacokinetic Properties

When intravenous (IV) basiliximab was added to dual-immunotherapy (cyclosporin microemulsion and corticosteroids), its maximum serum concentration (Cmax) and the area under the serum concentration-time curve (AUC) exhibited dose proportionality. Cmax values in adult renal transplant recipients after an initial 20mg dose on the day of transplantation ranged from 5.2 to 8.7 μg/mL and from 6.9 to 13.1 μg/mL after the second dose. The AUC reported with this regimen was 104 μg · day/mL (period not reported).

The basiliximab serum concentration was maintained above 0.2 μg/mL over the interdose period (days 0–4 in the majority of patients.

In renal transplant recipients, basiliximab has a small volume of distribution in the central compartment (3.5–3.7L); however, the volume of distribution at steady state is larger (5.4–8.0L). Basiliximab also exhibits a low total body clearance (17.3–36.7 mL/h) and a long elimination half-life (7.4–8.2 days) in adult renal transplant recipients. Values of these parameters varied (18.6–41.4%) between patients; but differences in weight, age or sex accounted for <10% of the interpatient variability.

The pharmacokinetic profile of basiliximab (12 mg/m2 or 10mg for patients weighing <40kg or 20mg for those weighing ≥40kg) in paediatric renal transplant recipients was generally similar to that observed in adults. However, the clearance of basiliximab in infants and children was slower than that seen in adults but is independent of age, weight or body surface area.

The addition of azathioprine or MMF to dual-immunotherapy resulted in significant changes to some of the pharmacokinetic parameters of basiliximab; however, adjustments to the basiliximab dosage are not needed.

Limited data in renal transplant recipients suggest significant drug interactions between basiliximab and cyclosporin (formulation not specified) or tacrolimus; the study authors suggested that increased drug monitoring and adjustments to the dosage of cyclosporin or tacrolimus may be required in basiliximab recipients. However, no formal recommendations are available.

Clinical Efficacy

Basiliximab induction therapy (20mg within 2 hours prior to transplantation surgery and 4 days after surgery administered by IV bolus injection or a 20 to 30-minute infusion) in combination with dual-(cyclosporin microemulsion and corticosteroids) or azathioprine-based triple-immunotherapy (azathioprine, cyclosporin microemulsion and corticosteroids) significantly decreased the incidence of acute organ rejection episodes and biopsy-confirmed acute rejection episodes compared with placebo at 6 or 12 months in randomised, double-blind, multicentre trials in adult renal transplant recipients. Basiliximab in combination with MMF-based triple-immunotherapy resulted in a 42.5% reduction in the incidence of acute rejection episodes (all of which were biopsy-confirmed) at 6 months compared with placebo; however, the difference between the two treatment groups was not significant.

The graft survival rate 12 months after transplantation in basiliximab recipients was similar to that in placebo recipients in trials using baseline dual- or triple-immunotherapy. Patient survival after 12 months was also similar in the two treatment groups in dual- or triple-immunotherapy trials. Basiliximab was also associated with a numerically lower rate of treatment failure (defined as an acute rejection episode, death or graft loss) than placebo after 6 months; this difference between the treatment groups reached statistical significance in two studies.

A pooled analysis of two 4-year extension phases of two 12-month placebo-controlled trials found that significantly more patients receiving basiliximab were free from treatment failure (the combined endpoint of death, graft loss or acute rejection) 3 years after transplantation than placebo recipients; however, there was no significant difference between the two treatment groups for this endpoint 5 years after transplantation. A small, randomised, single-centre study also reported a significantly lower incidence of acute rejection after 3 years in patients receiving induction therapy with basiliximab than in patients receiving no induction therapy; however, there was no significant difference between the two treatment groups in the incidence of subclinical and chronic rejection, graft function, or graft and patient survival.

Data on the efficacy of induction therapy with basiliximab compared with lymphocyte-depleting antibodies are limited. In renal transplant recipients, basiliximab was as effective as equine antithymocyte globulin (ATG), and had similar efficacy to or greater efficacy than muromonab CD3 in the prevention of acute rejection episodes. One trial published in full showed that basiliximab was similar to rabbit antithymocyte globulin (RATG) in terms of biopsy-confirmed rejection rate in renal transplant recipients at relatively low risk of acute rejection; however, the preliminary (9.8-month) results of a larger study (reported as an abstract) suggest that RATG was superior to basiliximab in high-risk renal transplant recipients. Generally, no significant differences were apparent in graft and patient survival or treatment failure at 12 months between the basiliximab treatment group and the various comparators.

A number of comparative studies have suggested that the combination of basiliximab and a corticosteroid-sparing regimen has generally similar efficacy to that of standard corticosteroid therapies. Basiliximab in combination with a calcineurin inhibitor-sparing regimen was significantly more effective at reducing biopsy-confirmed acute rejection than basiliximab plus a standard or calcineurin inhibitor regimen.

Induction therapy with basiliximab was also effective in elderly renal transplant recipients or patients with either type 1 or type 2 diabetes mellitus.

Retrospective studies in paediatric renal transplant recipients suggest that the efficacy of basiliximab is similar to that of baseline immunosuppression alone, ATG or antilymphocyte globulin (ALG). The incidence of acute rejection episodes was generally similar with basiliximab induction therapy and baseline immunosuppression alone, ATG or ALG. The renal function and rates of graft and patient survival of those treated with basiliximab, ATG or ALG were also similar.

Tolerability

Data from numerous clinical trials indicate that induction therapy with basiliximab is generally well tolerated in adult renal transplant recipients. First-dose reactions, cytokine release syndrome and local adverse events related to the administration of basiliximab were not reported in clinical trials. The incidence of any adverse event, severe adverse events or adverse events considered related to the study drug were similar in basiliximab and placebo recipients. The most common adverse events in both basiliximab and placebo recipients were gastrointestinal disorders.

Basiliximab recipients experienced a similar incidence of any adverse events or severe adverse events as ATG or RATG recipients. Numerically fewer patients receiving basiliximab experienced adverse events considered to be related to the study drug than those receiving ATG (statistical analysis not reported), and significantly fewer basiliximab recipients experienced adverse events related to the study drug than RATG recipients. In addition, the incidences of fever and leukopenia were significantly lower in basiliximab recipients than in those receiving RATG.

Rare instances of hypersensitivity generally following a second course of induction therapy with basiliximab have been reported in post-marketing surveillance.

Treatment with basiliximab did not result in an increase in the incidence of infections (including cytomegalovirus [CMV]) compared with placebo. The most common type of infection with basiliximab or placebo was urinary tract infection. The incidence of infection was also similar with basiliximab and ATG or RATG. The incidence of CMV infection was reported as similar for basiliximab and ATG or RATG in two trials but, in another trial, the incidence of CMV infection was significantly lower with basiliximab than with RATG. Malignancies and post-transplant lymphoproliferative disorders were rare in patients receiving basiliximab, with incidences similar to those seen in placebo recipients at 12 months and 5 years after transplantation. Additionally, there was no significant difference in the incidence of malignancy between the basiliximab and ATG or RATG treatment groups.

Basiliximab was well tolerated in combination with corticosteroid-withdrawal or corticosteroid-free regimens.

Overall, basiliximab had similar tolerability to placebo in a pooled analysis of patients with diabetes mellitus. Limited data suggest that basiliximab was better tolerated than ALG or ATG in paediatric patients and better tolerated than muromonab CD3 in elderly patients.

Pharmacoeconomic Considerations

In three pharmacoeconomic cost-effectiveness studies in renal transplant recipients, induction therapy with basiliximab demonstrated significant clinical efficacy but did not increase overall treatment costs over 6 or 12 months relative to treatment with placebo. With basiliximab, the cost per suspected rejection episode avoided was $US9823 in one study, and the cost per treatment failure avoided was $US4669 in another study (year of cost 1996 for both). Two economic models using data from placebo-controlled trials also suggested that induction therapy with basiliximab results in total cost savings.

A cost utility model comparing basiliximab with other immunosuppressive agents found that the cost per quality-adjusted life-year gained with basiliximab induction therapy was similar to that of daclizumab, but lower than that of muromonab CD3. Additionally, a French cost-minimisation study found that the cost of induction therapy with basiliximab was numerically higher than the cost of RATG (statistical analysis not reported); however, the cost of initial hospitalisation was significantly lower in patients receiving basiliximab than in those receiving RATG. Furthermore, in another cost analysis, the total costs of treatment were lower for patients receiving basiliximab than for those treated with ATG. However, there was no difference between the two treatment groups in patient-assessed health-related quality of life within 12 months of transplantation.

Dosage and Administration

Basiliximab is approved in the US and Europe for the prophylaxis of acute organ rejection in renal transplant recipients. It should be administered in combination with standard immunosuppressants. The recommended dosage of basiliximab for adult and paediatric (bodyweight ≥35kg) renal transplant recipients is 20mg administered within 2 hours prior to transplant surgery with a second dose 4 days later. The recommended dosage in paediatric patients weighing <35kg is basiliximab 10mg administered at the same timepoints. No dosage adjustments are necessary for elderly patients. Basiliximab may be administered by IV bolus injection or IV infusion over 20–30 minutes.

Basiliximab is contraindicated in patients who are hypersensitive to the preparation. If a hypersensitivity reaction occurs, treatment with basiliximab should be permanently discontinued and the reaction treated. In the US it is recommended that patients previously treated with basiliximab be re-exposed to a subsequent course of basiliximab therapy only with extreme caution.

Patients receiving immunotherapy are at increased risk of developing PTLD and infections, and should be monitored accordingly.

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.dis International LimitedMairangi BayNew Zealand