Drugs

, Volume 63, Issue 24, pp 2803–2835

Basiliximab

A Review of its Use as Induction Therapy in Renal Transplantation

Authors

    • dis International Limited
  • Gillian M. Keating
    • dis International Limited
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.

1. Introduction

Kidney transplants have become a routine procedure for the treatment of renal failure. It is estimated that each year more than 25 000 patients undergo renal transplantation worldwide.[1] However, graft rejection remains a serious problem.[1] Immunosuppressive agents are used to prevent graft rejection. The goals of immunosuppression are to maximise graft and patient survival while maintaining the immune response of the patient and minimising adverse events, such as infection or malignancy, associated with immunosuppressive agents.[1,2]

Induction therapy with lymphocyte-depleting antibody preparations (antilymphocyte globulin [ALG], equine antithymocyte globulin [ATG], rabbit antithymocyte globulin [RATG] or muromonab CD3) is thought to inhibit the immune response by nonspecifically reducing T lymphocytes.[37] It should be noted that RATG is approved for use in the treatment of acute renal graft rejection, but not for use as an induction agent.[7] More selective immunosuppression was achieved with the development of monoclonal antibodies that specifically bind to the α subunit (also known as Tac or CD25) of the interleukin (IL)-2 receptor (IL-2Rα) present on activated T lymphocytes.[3,4,8,9] These agents inhibit the binding of the cytokine IL-2 to the IL-2Rα, thus inhibiting IL-2—mediated activation and proliferation of T lymphocytes and ultimately prevent graft rejection without affecting the pre-existing and nonspecific immune responses of the recipient.[3,4,8,9]

Early clinical trials were conducted with murine or rat anti-IL-2Rα monoclonal antibodies.[3,8,10] Although results were favourable, the high immunogenicity and short half-life of these agents limited their clinical application.[3,8,10] Chimeric and humanised monoclonal anti-IL-2Rα antibodies have been developed to improve the tolerability and extend the half-lives of these agents.[3,8,10]

Basiliximab (Simulect®1) is a chimeric (human/murine) monoclonal antibody that specifically inhibits T lymphocyte proliferation by binding to IL-2Rα. It is licensed in the US and Europe for the prophylaxis of acute organ rejection in adult and paediatric renal transplant recipients in combination with dual-immunotherapy including cyclosporin microemulsion and corticosteroids, or triple-immunotherapy including cyclosporin microemulsion and corticosteroids plus azathioprine or mycophenolate mofetil (MMF). This article reviews the efficacy and tolerability of induction therapy with basiliximab in the prevention of acute rejection of renal transplants.

2. Pharmacodynamic Properties

Basiliximab is a chimeric immunoglobulin G (IgG) monoclonal antibody in which the variable regions of a murine monoclonal antibody (RFT5) that bind specifically to IL-2Rα are combined with the constant regions of human IgG1 heavy and κ light chains.[11,12] In this way, basiliximab combines the specificity and high affinity of RFT5 for IL-2Rα with reduced immunogenicity compared with murine or rat antibodies.[13]

2.1 Mechanism of Action

Basiliximab largely exerts its immunosuppressive effect by specifically binding with high affinity (apparent affinity constant of 1 × 1010 M−1)[12] to IL-2Rα on the surface of activated T lymphocytes,[14] thereby competitively inhibiting IL-2—mediated activation and proliferation of T lymphocytes.[11,12] In vitro studies using human tissues indicate that basiliximab binds only to activated lymphocytes[12] and macrophages/monocytes;[15] however, resting T lymphocytes that do not express IL-2Rα are not affected by basiliximab.[13] While it is present in the circulation, basiliximab impairs the response of the immune system to antigenic challenges; however, it is not known whether this affects the long-term ability of the immune system to respond to antigens first encountered during immunosuppression with basiliximab.[12]

IL-15 and IL-7 are also implicated in the process of acute graft rejection.[16] The binding of basiliximab to IL-2Rα caused the down-regulation of the expression of IL-2Rβ/IL-15Rβ chain in 29 renal transplant recipients.[16] This resulted in the suppression of signalling by IL-15R and led to impaired IL-15—dependent proliferation.[16] However, basiliximab had no effect on IL-7—dependent peripheral blood mononuclear cell proliferation.[16]

2.2 Interleukin-2 Receptor Binding

Saturation of IL-2Rα on circulating T lymphocytes in renal transplant recipients occurs at serum concentrations of basiliximab >0.2 μg/mL.[12,15,17] When concentrations fall below this threshold, the number of circulating T lymphocytes expressing free IL-2Rα returns to normal levels within 1–2 weeks.[12,15] A dose-finding study[11] found no benefit from treatment (in terms of acute rejection) when IL-2Rα was suppressed for longer than 1 month.

Basiliximab saturates IL-2Rα rapidly in vivo.[11,18] The percentage of T lymphocytes expressing the IL-2 binding site (detected by staining with a murine antibody specific for the IL-2 binding site of IL-2Rα [anti-CD25A]) in a representative patient treated with basiliximab 10mg on days 0, 2, 6, 11, 17 and 24 fell from approximately 25% to <5% after the first infusion of basiliximab.[11] Similarly, in a study in 14 paediatric renal transplant recipients who received basiliximab 10 (patients weighing <40kg) or 20 mg/dose (patients weighing >40kg), IL-2Rα saturation was observed within 24 hours of the first dose.[18]

After administration of the recommended dosage of basiliximab (an intravenous [IV] infusion of basiliximab 20mg within 2 hours prior to transplantation surgery and a second dose 4 days later) in combination with dual-immunotherapy comprising cyclosporin microemulsion plus corticosteroids, the mean duration of IL-2Rα suppression in adult renal transplant recipients ranged from 36–49 days.[1921] The mean duration of IL-2Rα saturation in adult renal transplant recipients receiving dual-immunotherapy in one trial (36 days)[19] was significantly extended by the addition of azathioprine (50 days) or MMF (59 days) [p < 0.001 vs dual-immunotherapy for both].[22] The mean duration of IL-2Rα saturation in paediatric patients receiving basiliximab 12 mg/m2 or a fixed dose of 10 or 20mg dependent on age (details not reported) or bodyweight (those <40kg bodyweight received basiliximab 10mg and those ≥40kg bodyweight received basiliximab 20mg) on days 0 and 4 was 31–42 days.[18,23,24]

2.3 Effect on T Lymphocytes

Basiliximab reduces the number of circulating T lymphocytes expressing IL-2Rα.[11] In a preliminary study, treatment with basiliximab (2.5–25mg on days 0, 2, 6, 11, 17 and 24) resulted in a significant reduction in the number of circulating T lymphocytes expressing IL-2Rα (detected by murine antibodies specific for the IL-2 binding site [anti-CD25A] or for a non-IL-2 binding site [anti-CD25B] of the IL-2Rα; p < 0.0001).[11] The mechanism for the reduction in T lymphocytes expressing IL-2Rα is not known; however, the study authors suggest these cells may be eliminated or modified by the shedding or stripping of IL-2Rα.[11]

In two other studies, the percentage of T lymphocytes expressing IL-2Rα prior to therapy with basiliximab in adult renal transplant recipients was 18–44%.[21,25] However, immediately after treatment with basiliximab, the percentage of cells expressing IL-2Rα fell to <3%[21,25] and, in one study, remained at this level for a mean 51 days.[21] Similarly, the percentage of T lymphocytes expressing IL-2Rα was significantly lower after saturation of IL-2Rα with basiliximab than at the time of desaturation (3–6 weeks after the last dose of basiliximab) [6.5% vs 12.3%; p = 0.003] in a study in paediatric renal transplant recipients.[18]

However, there were no significant differences in the total level of circulating lymphocytes, the number of each cell subtype (e.g. natural killer cells, B lymphocytes, T helper cells, cytotoxic T cells and δ-positive T lymphocytes) or in the number of T lymphocytes expressing activation markers other than IL-2Rα (CD26, CD38, CD54, CD69 and HLA-DR) observed by flow cytometry in patients after treatment with basiliximab compared with those receiving no induction therapy.[11,18]

2.4 Immunogenicity

Limited data from clinical trials reported in the US and European prescribing information indicate that basiliximab has a low potential for immunogenicity.[12,15] Of 339 renal transplant recipients treated with basiliximab and tested for the presence of anti-idiotype antibodies, four patients developed an anti-idiotype antibody response; however, the presence of these antibodies did not alter the clinical response to treatment.[12] In one study, 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 subsequent muromonab CD3, suggesting the high antibody response is due to muromonab CD3. However, the use of basiliximab does not exclude the subsequent use of muromonab CD3 or other murine antilymphocyte antibody preparations.[12,15]

3. Pharmacokinetic Properties

The pharmacokinetic profile of IV basiliximab in combination with baseline immunosuppression has been evaluated in a number of studies in adult[17,1922,25] and paediatric[18,23] renal transplant recipients. Doses of basiliximab administered to patients in these studies ranged from 5 to 60mg.[1723,25] An overview of the pharmacokinetic profile for basiliximab is presented in table I.
https://static-content.springer.com/image/art%3A10.2165%2F00003495-200363240-00009/MediaObjects/40265_2012_63242803_Tab1.jpg
Table I

Mean pharmacokinetic parameters of intravenous (IV) basiliximab in adult and paediatric renal transplant recipients. Patients also received dual- or triple-immunotherapy

3.1 Adults

In 11 adult renal transplant recipients given the recommended regimen of basiliximab (an IV infusion of basiliximab 20mg within 2 hours prior to transplantation surgery and a second dose 4 days later) in combination with baseline dual-immunotherapy, the maximum serum concentration (Cmax) of basiliximab (measured by ELISA) ranged from 5.2 to 8.7 μg/mL after the first dose and from 6.9 to 13.1 μg/mL after the second dose.[21] In the same study, the area under the serum concentration-time curve (AUC; period not reported) was 104 μg ⋅ day/mL.[21] Basiliximab exhibited dose-proportional Cmax and AUC values in renal transplant recipients (total n = 67) given 40 or 60mg[17] or 20–60mg[25] of basiliximab.

In one dual-immunotherapy study,[19] after administration of the recommended regimen of basiliximab, the mean serum basiliximab concentration over the interdose period (days 0–4) was 1.7 μg/mL; during this period, 97% of patients maintained a basiliximab serum concentration >0.2 μg/mL (the serum concentration of basiliximab at which IL-2Rα on circulating T lymphocytes is saturated in renal transplant recipients; section 2.2). All patients receiving MMF-based triple-immunotherapy in combination with basiliximab maintained a basiliximab serum concentration above the IL-2Rα saturating threshold during the interdose period (mean serum basiliximab concentration 2.2 μg/mL); results for basiliximab in combination with azathioprine-based triple-immunotherapy were not reported.[22]

Basiliximab initially distributes within a relatively restricted volume.[1921] In adult renal transplant recipients given the recommended regimen of basiliximab in combination with dual-immunotherapy (total n = 220), the volume of distribution in the central compartment (Vc) was 3.5–3.7L, which was consistent with plasma volume.[1921] However, the volume of distribution at steady state (Vss) was 5.4–8.0L, which was greater than that of blood, indicating distribution outside the circulatory system.[1921]

Data concerning the metabolism of basiliximab are not available. In adult renal transplant recipients, basiliximab exhibited slow total clearance (CL) from the body (17.3–36.7 mL/h) and a long terminal elimination half-life (t½; 7.4–8.2 days).[1921]

In population-based pharmacokinetic analyses, moderate interpatient variability (18.6–41.4%) was observed in some pharmacokinetic parameters, such as Vss, t½ and CL.[19,20] However, bodyweight, age or sex accounted for <10% of the interpatient variability.[19,20]

3.2 Paediatric Patients

In a study in paediatric renal transplant recipients (aged 1–16 years), 27 patients received two fixed doses of basiliximab (those <40kg bodyweight received basiliximab 10mg and those ≥40kg bodyweight received basiliximab 20mg) and another 12 patients received 12 mg/m2 (not to exceed 20mg) on days 0 and 4.[23] The mean Cmax and AUC for the fixed-dose regimen were 5.7 μg/mL and 59 μg ⋅ day/mL; the corresponding values for the 12 mg/m2 dose were 5.9 μg/mL and 43 μg ⋅ day/mL.[23]

The serum basiliximab concentrations were >0.2 μg/mL (indicative of IL-2Rα saturation on circulating T lymphocytes; section 2.2) for the interdose period (mean 1.0 μg/mL prior to the second dose) in patients receiving either the fixed dose (according to bodyweight) or 12 mg/m2.[23]

The volume of distribution, t½ and CL are not dose dependent, so data from patients receiving basiliximab 10 or 20 mg/dose (according to bodyweight) or 12 mg/m2 (n = 39) were pooled for infants and children (aged <12 years) or adolescents (aged 12–16 years) [table I] The Vc increased with age, weight and body surface area, whereas the Vss and t½ were independent of these factors.[23] The clearance of basiliximab in infants and children was slower than that previously observed in adults (table I), but is independent of age, weight or body surface area.[23]

In this pharmacokinetic study, 2 of 36 patients evaluable for the presence of antibodies had detectable levels of anti-idiotype antibody; however, the clearance of basiliximab and duration of IL-2Rα saturation were unaffected by the presence of this antibody.[23]

3.3 Drug Interactions

Compared with dual-immunotherapy comprising cyclosporin microemulsion plus corticosteroids,[19] triple-immunotherapy including the addition of azathioprine or MMF significantly altered (p < 0.001) certain basiliximab pharmacokinetic parameters such as t½ and CL[22] (table I) [the dual-immunotherapy regimen and triple-immunotherapy regimens were evaluated in different studies]. The development of anti-idiotype antibodies in one recipient of basiliximab plus MMF-based triple-immunotherapy did not affect basiliximab clearance or reduce the duration of IL-2Rα saturation.[22] This study did not report the effect basiliximab had on the pharmacokinetic profiles of azathioprine or MMF. However, no dosage adjustments are necessary when basiliximab is combined with triple-immunotherapy regimens including azathioprine or MMF (section 7).

Limited data have suggested there are significant drug interactions between basiliximab and the calcineurin inhibitors cyclosporin (formulation not specified)[26] or tacrolimus.[27] A retrospective analysis found that despite a lower required dosage of cyclosporin (adjusted daily to achieve trough levels of 200–300 μg/L), cyclosporin trough blood concentrations and evidence of cyclosporin toxicity were greater within the first 10 days of transplantation in 24 paediatric patients (mean age 7.5 years) receiving basiliximab compared with 15 paediatric renal transplant recipients (mean age 9.7 years) receiving no induction therapy.[26] Almost all (92%) basiliximab recipients had cyclosporin trough blood concentrations greater than 300 μg/L compared with 60% of patients receiving no induction therapy.[26] However, 28–50 days after transplantation, the blood concentrations of cyclosporin in patients treated with basiliximab declined significantly (p < 0.0001 vs controls), and the cyclosporin dosage required to maintain trough concentrations of cyclosporin was 20% higher in these patients than in those receiving no induction therapy.[26] Conversely, a prospective study in paediatric renal transplant recipients[24] found no evidence of an interaction between basiliximab and cyclosporin microemulsion, so caution is necessary for the interpretation of these results.

A similar interaction was found in another small retrospective analysis in which adult renal transplant recipients received basiliximab and tacrolimus (n = 12) or ATG and tacrolimus (n = 8).[27] Trough blood concentrations of tacrolimus 3 days after transplantation increased by 63% and tacrolimus trough blood concentrations normalised to dose were significantly higher in patients treated with basiliximab than in patients receiving ATG (p < 0.05).[27] Half of the basiliximab recipients had trough blood concentrations of tacrolimus greater than 20 ng/mL compared with 25% of ATG recipients, and the tacrolimus dosage for the first week following transplantation was significantly lower for basiliximab recipients than for ATG recipients (p < 0.05).[27]

Although the exact mechanism for these interactions is unclear, the authors of these studies suggest that basiliximab may cause an IL-2Rα—induced alteration of cyclosporin or tacrolimus metabolism by downregulating the hepatic cytochrome P450 system.[26,27] The authors suggest that increased drug level monitoring and dosage adjustments of cyclosporin or tacrolimus may be required in transplant recipients receiving basiliximab in order to reduce the risk of adverse events caused by drug toxicity and of an acute rejection episode.[26,27] However, the basiliximab prescribing information does not recommend any adjustments to the dosage of calcineurin inhibitors.[12,15]

4. Clinical Efficacy

The clinical efficacy of induction therapy with IV basiliximab in the prevention of acute renal graft rejection when combined with existing primary immunosuppression, including a calcineurin inhibitor (cyclosporin microemulsion or tacrolimus) and corticosteroids with or without azathioprine or MMF, has been assessed in numerous clinical trials in both adults[2841] and paediatric patients.[4245] The efficacy of basiliximab as an adjunct in calcineurin inhibitor-[46] and corticosteroid-sparing[4749] regimens has also been studied. Numerous trials of varying design have been conducted; this review focuses on data from well designed trials where available (most studies were randomised and of double-blind[2832] or nonblind[34,35,37,47,48] design; some studies did not report the blinding protocol used[33,36,49]. Data from retrospective trials are also included.[3845] Caution should be used in the interpretation of the results of retrospective trials using historical controls, as the treatment groups may not be well matched and clinical protocols (including surgical techniques) may have altered or improved in the interval. Not all trials have been fully published; accordingly, preliminary reports and abstracts of some trials are discussed.[30,36,40,41,48,49]

Patients included in these trials were generally recipients of a first or second HLA-mismatched renal transplant from a cadaveric or living donor.[28,29,3135,37,46,47,49] Patient and donor characteristics, including age, sex and race, were generally similar between treatment groups.[28,29,3135,37,47,48] In addition, patient populations were generally similar with regards to the causes of renal failure and the presence of any comorbidities.[29,3235,37,47,48] However, in some trials there was a lack of specific information on patient demographics, the dosage regimens of baseline immunotherapy or the timing of sampling.[36,3841,46,49]

Exclusion criteria generally included a second[35,37] or third and subsequent renal transplant,[31,32,34] any other previous organ transplantation,[29,31,32,34,35,47] a multiple organ transplantation,[29,32,34,35,47] planned induction with ALG, ATG, or muromonab CD3,[31,32,35,47] current positive T-cell crossmatch,[31,32,35,47] blood group incompatibility with the donor,[31,32,35] HIV-positive status,[31,32,34] active hepatitis,[31,32] malignancy within the last 5 years,[32,34,35,47] myocardial infarction,[34] cardiac arrhythmias,[34] HLA-matched donor,[31,32,34,37] pregnancy or an unwillingness of women of child-bearing age to use contraception.[28,29,31,32,34,35,37] Recipients of other investigational drugs within 1 month of study entry,[29,31,32,34,35,47] or those who received any immunosuppressive investigational drug within 6 months of study entry,[32,35] or antibacterial treatment for a severe active infection[29] were also excluded.

The primary efficacy endpoint in clinical trials was generally the incidence of post-transplant acute rejection episodes (total and/or biopsy-confirmed) at 6 or 12 months.[2832,3437,3943,4549] Secondary endpoints varied, but generally included graft and patient survival rates,[2832,34,35,3740,4249] percentage of patients with graft rejection requiring treatment with antilymphocyte and/or calcineurin inhibitor therapy,[28,29,31,32,34,35,47] histological severity of acute graft rejection episodes (assessed by Banff classification criteria 1993[50] and 1997[51],[28,29,31,32,34,35,46,47] graft function[28,35,4346,48,49] and treatment failure (defined as an acute rejection episode, death or graft loss).[28,31,32,3436] The long-term efficacy of basiliximab has been reported in a 3-year randomised, single-centre study[33] and in a pooled analysis of 5-year data from two placebo-controlled studies (two 12-month core trials with 4-year nonblind extension phases) which are available as data on file.[52]

Tolerability, including the incidence of infections and other adverse events, is reviewed in section 5.

4.1 Adult Patients

Owing to the availability of a large amount of comparative data in adult patients, the results of noncomparative trials using standard immunosuppression[5360] or a calcineurin inhibitor-[6163] or corticosteroid-sparing[64,65] regimens in adults are not discussed in this section.

The regimen of basiliximab administered to adult renal transplant recipients in clinical trials consisted of a single dose of IV basiliximab 20mg within 2 hours prior to renal transplantation and a second dose 4 days after transplantation.

4.1.1 Comparisons with Placebo

Data in this section are primarily from five well designed, randomised, double-blind, multicentre, placebo-controlled trials[2832] including a total of approximately 1500 recipients of renal transplants; data are available for 6 and/or 12 months after transplantation. Long-term data is available from a pooled analysis[52] of two 4-year nonblind extension phases of two 12-month placebo-controlled trials by Kahan et al.[28] and Nashan et al.,[29] and a small, randomised, 3-year study by Sheashaa et al.,[33] in which control patients received no induction therapy.

In the placebo-controlled trials, patients were randomised to receive either an IV infusion over 20–30 minutes[28,29] or an IV bolus injection[3032] of basiliximab or placebo. All patients received baseline immunotherapy of cyclosporin microemulsion plus corticosteroids for the duration of the studies. Cyclosporin microemulsion was administered perioperatively to maintain trough blood concentrations within the therapeutic range, and corticosteroids were generally administered in accordance with the institutional protocol. In two trials, baseline therapy was supplemented with azathioprine (1–2 mg/kg/day);[30,31] MMF (2 g/day) was administered in a third.[32]

The results of the intent-to-treat (ITT) analyses of placebo-controlled studies are summarised in table II.
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Table II

Clinical efficacy of induction therapy with basiliximab (BAS) in the prevention of acute renal graft rejection in randomised, double-blind, multicentre, placebo (PL)-controlled trials. Adult patients (pts) were randomised to receive an intravenous (IV) bolus injection or a 20 to 30-minute IV infusion of BAS 20mg or PL within 2 hours prior to renal transplantation and 4 days after transplantation in addition to dual- or triple-immunotherapy.a Results are from intent-to-treat (ITT) analyses at 6 or 12 months

Acute Rejection

The addition of basiliximab to dual-immunotherapy significantly decreased the incidence of any acute rejection episodes and biopsy-confirmed acute rejection episodes compared with placebo at 6 and 12 months (table II).[28,29]

Similarly, induction therapy with basiliximab in combination with azathioprine-based triple-immunotherapy significantly decreased acute rejection episodes and biopsy-confirmed acute rejection episodes compared with placebo at 6 months (table II).[30,31] Ponticelli et al.[31] also reported the incidence of acute rejection episodes (21.4% vs 36.0%) and biopsy-confirmed acute rejection episodes (19.0% vs 30.2%) at 12 months in patients receiving basiliximab or placebo in addition to azathioprine-based triple-immunotherapy; however, p values were not reported.

In the trial that used MMF-based triple-immunotherapy,[32] the incidence of acute rejection episodes (all of which were biopsy-confirmed) at 6 months was 42.5% lower with basiliximab than with placebo (table II). Although the results were numerically different, the differences were not statistically significant; however, it should be noted that the study was not powered to detect a statistical difference between treatment groups.

In the studies that reported a statistical analysis,[28,29,31] there was no significant difference between those receiving basiliximab or placebo for the histological severity of biopsy-confirmed acute rejection episodes (assessed by Banff criteria). However, in a trial using MMF-based triple-immunotherapy, the percentage of patients with moderate or severe biopsy-confirmed acute rejection episodes was numerically lower in those receiving basiliximab than those receiving placebo (5.1% vs 18.8%; statistical analysis not reported).[32]

In one dual-immunotherapy trial,[28] basiliximab was associated with a significant reduction in the mean number of rejection episodes per patient compared with placebo (quantitative data not reported; p = 0.005), and in an azathioprine-based triple-immunotherapy trial,[31] significantly fewer basiliximab recipients experienced two or more acute rejection episodes than those receiving placebo (4.2% vs 7.0%; p = 0.026). However, the dual-immunotherapy trial by Nashan et al.[29] found no significant difference in the number of patients who experienced more than one acute rejection episode.

Graft Function

The improvement in renal graft function after treatment with basiliximab was similar to,[29,32] or more rapid[28] than that with placebo. In a dual-immunotherapy trial,[28] a significantly higher percentage of patients receiving basiliximab produced urine in the operating room compared with those receiving placebo (94% vs 87%; p = 0.03). In the MMF-based triple-immunotherapy trial by Lawen et al.,[32] creatinine clearance was significantly higher (p = 0.034) with basiliximab than with placebo at week 2, but results were similar from week 4 onwards. Similarly, in the dual-immunotherapy trial by Nashan et al.,[29] creatinine clearance was similar in basiliximab and placebo recipients from week 4 onwards. In contrast, Kahan et al.[28] (dual-immunotherapy) found that those receiving basiliximab showed significantly higher (p < 0.05) mean calculated creatinine clearance over the 12-month follow-up, except at week 12.

However, in studies in which it was reported, there was no significant difference for the incidence of delayed graft function (DGF; defined as the need for dialysis, urine output <30 mL/h, or a decrease in the serum creatinine level at 24 hours after transplantation of <20% from the pretransplantation value,[32] or the need for haemodialysis within the first 7 postoperative days[28] between the basiliximab and placebo treatment groups when used in combination with dual- (15% vs 23%)[28] or MMF-based triple-immunotherapy (15.3% vs 23.4%).[32]

Graft and Patient Survival and Treatment Failure
The rate of graft survival at 12 months in patients receiving basiliximab was similar to that of placebo recipients in trials using dual-immunotherapy (table II).[28,29] The rate of graft survival in basiliximab and placebo recipients in trials using azathioprine-based triple-immunotherapy was similar at 6 (92.8% vs 90.8%)[30] or 12 months (90.5% vs 88.4%).[31] There was also no significant difference in the rate of graft survival at 6 or 12 months between basiliximab and placebo recipients in the trial using MMF-based triple-immunotherapy (94.9% vs 92.2% for both timepoints).[32] Reasons for graft loss from the largest dual-immunotherapy study[29] are shown in figure 1.
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Fig. 1

Causes of graft loss in renal transplant recipients 12 months after transplantation. Renal transplant recipients were randomised to double-blind treatment with an intravenous infusion of basiliximab 20mg (n = 190) or placebo (n = 186) administered within 2 hours prior to surgery and again on day 4 in a multicentre trial.[29] All patients received baseline immunosuppression with cyclosporin microemulsion and corticosteroids.

Patient survival at 12 months was similar for those receiving basiliximab or placebo in combination with dual-immunotherapy (table II).[28,29] There was also no significant difference in patient survival among patients receiving basiliximab or placebo in combination with azathioprine-based triple-immunotherapy at 6 (96.7% vs 95.5%)[30] or 12 months (97.6% vs 97.1%).[31] In the trial using MMF-based triple-immunotherapy, patient survival was 100% in both the basiliximab and placebo treatment groups at 12 months after transplantation.[32]

In trials that reported the composite endpoint of treatment failure,[28,31,32] basiliximab was associated with a lower rate of treatment failure than placebo (table II), and this difference between the treatment groups reached statistical significance in one dual-immunotherapy trial (p = 0.001)[28] and one azathioprine-based triple-immunotherapy trial (p < 0.01).[31]

Requirement for Corticosteroid and/or Antilymphocyte Therapy

In both dual-immunotherapy trials[28,29] and one azathioprine-based triple-immunotherapy trial,[31] the lower acute rejection rate observed in basiliximab recipients resulted in significantly lower mean daily dosages of corticosteroids for these patients than the amounts administered to placebo recipients at 2 and 4 weeks after transplantation (p < 0.05); these timepoints coincided with the peak onset of acute rejection episodes. At other timepoints, there were no significant differences in the corticosteroid dosages between the treatment groups.[28,29,31]

Significantly fewer patients receiving basiliximab experienced a corticosteroid-resistant rejection episode requiring treatment with antilymphocyte therapy (ALG, ATG or muromonab CD3) than those receiving placebo in dual-immunotherapy trials in the first 6 (10.0% vs 23.1%; p < 0.001)[29] or 12 months following transplantation (20.2% vs 29.9%; p < 0.05);[28] however, there was no significant difference between the two treatment groups at 6 months following transplantation in an azathioprine-based triple-immunotherapy trial (5.4% vs 9.9%)[31] or in the MMF-based triple-immunotherapy trial (5.1% vs 15.6%).[32]

Similarly, significantly fewer basiliximab than placebo recipients experienced a corticosteroid-resistant rejection episode requiring treatment with antibody and/or other immunosuppressive agents such as tacrolimus, MMF or azathioprine at 12 months in a dual-immunotherapy trial (25.4% vs 41.6%; p = 0.001);[28] however, the difference was not significant between the two treatment groups at 6 months in patients receiving azathioprine-based triple-immunotherapy (9.5% vs 14.0%).[31]

Long-Term Data

A pooled analysis (total n = 722) of two 4-year nonblind extension phases of the 12-month placebo-controlled studies by Kahan et al.[28] and Nashan et al.[29] found that significantly more basiliximab recipients were free from the combined endpoint of death, graft loss or acute rejection, as assessed by Kaplan Meier estimates, than those receiving placebo 3 years after transplantation surgery (53% vs 45%; p = 0.025).[52] However, there was no significant difference between the treatment groups for this endpoint 5 years after transplantation (46% vs 42%).[52]

Additional long-term (3-year) data are available from a single-centre study in which renal transplant recipients were randomised to receive induction therapy with basiliximab (n = 50) or no induction therapy (control patients; n = 50) in combination with standard azathioprine-based triple-immunotherapy.[33] The incidence of acute rejection during the 3-year follow-up was significantly lower in basiliximab recipients than control patients (52% vs 72%; p = 0.039).[33] However, after 3 years’ follow-up, there was no significant difference between the two treatment groups for subclinical (2% vs 0%) or chronic rejection (4% vs 12%), or graft function as assessed by serum creatinine (1.51 vs 1.56 mg/dL) or creatinine clearance (76.56 vs 72.26 mL/min).[33] In addition, there was no significant difference between the two treatment groups for graft survival (96% vs 92%) or patient survival (100% vs 98%) 3 years after transplantation.[33]

Results of Meta-Analyses

Two meta-analyses[66,67] evaluating the efficacy of basiliximab in the prevention of acute organ rejection in renal transplantation have been published: one using data from randomised trials comparing monoclonal IL-2Rα antibodies with placebo or no induction therapy in renal transplant recipients (n = 1816),[66] and another including studies comparing basiliximab with placebo in renal transplant recipients (n = 1185).[67] Both meta-analyses included four of the placebo-controlled basiliximab trials[28,29,31,32] previously reviewed in this section. The results of these meta-analyses confirmed that basiliximab was more effective than placebo in the reduction of acute organ rejection in renal transplant recipients 6 months after transplantation (acute organ rejection occurred in 25.9% vs 38.1%[66] and 28.8% vs 44.4% of patients;[67] p < 0.0001 for both comparisons). Keown et al.[67] also reported that 6 months after transplantation basiliximab significantly reduced the incidences of biopsy-confirmed acute rejection (25.1% vs 36.8%), corticosteroid-resistant rejection episodes requiring treatment with antibody therapy (10.7% vs 19.8%) and treatment failure (33.6% vs 48.7%) compared with placebo (p < 0.0001 for all comparisons). Calculated creatinine clearance was also significantly greater (by 3.04 mL/min) in basiliximab recipients than in placebo recipients (p = 0.02) 6 months after renal transplantation.[67] However, in both meta-analyses, there was no significant difference between basiliximab and placebo in the incidence of graft or patient survival 12 months after transplantation.[66,67]

Effect of Basiliximab on Cadaveric- or Living-Donor Transplant Recipients

The benefit of treatment with basiliximab in combination with cyclosporin microemulsion and corticosteroids was found in both cadaveric- and living-donor graft recipients.[68] A retrospective study[68] using data from the placebo-controlled trial by Kahan et al.[28] found that induction therapy with basiliximab significantly reduced the incidence of the first episode of acute rejection and the composite endpoint, treatment failure, compared with placebo in both cadaveric- and living-donor renal transplant recipients (p < 0.05 for all comparisons). Patient and graft survival rates for the recipients of cadaveric- or living-donor grafts were similar between treatment groups.[68] However, it should be noted that this study was not powered to detect statistical differences within demographic subgroups.[68]

4.1.2 Comparisons with Lymphocyte-Depleting Antibodies

Results of large (n ≥ 100 [ITT population]), prospective, randomised trials comparing the efficacy of basiliximab induction therapy with that of polyclonal antibodies (ATG and RATG) in renal transplant recipients are summarised in table III. However, it should noted that RATG is not approved for use as an induction agent.[7]
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Table III

Results of randomised, multicentre studies comparing basiliximab (BAS)a with equine antithymocyte globulin (ATG) or rabbit antithymocyte globulin (RATG) in combination with triple-immunotherapyb in adult renal transplant recipients. Results are from the intent-to-treat (ITT) analyses at 6 or 12 months

Equine Antithymocyte Globulin (ATG)

Data from a randomised, nonblind, multicentre trial found the efficacy of basiliximab similar to that of ATG (for dosage details, see table III).[34] The incidence (table III) and severity (using Banff classification criteria) of biopsy-confirmed rejection episodes were similar for basiliximab and ATG recipients; however, a numerically greater number of patients receiving ATG experienced two or more rejection episodes than basiliximab patients (8% vs 4%; statistical analysis not reported).[34] There were also no significant differences between the basiliximab and ATG treatment groups in the rates of graft and patient survival or treatment failure at 12 months (table III).[34]

Rabbit Antithymocyte Globulin (RATG)

A fully published randomised, nonblind, multicentre trial found that basiliximab in combination with MMF-based triple-immunotherapy using immediate cyclosporin microemulsion therapy (day 0 or 1) was as effective as RATG plus MMF-based triple-immunotherapy using delayed cyclosporin microemulsion therapy (2–10 days after transplantation) in the prevention of acute rejection episodes in renal transplant recipients at relatively low risk of acute rejection; however, it should be noted that this trial was not powered to demonstrate overall superiority of one regimen over another (for dosage details, see table III).[35] The rate of biopsy-confirmed rejection at 6 months was the same for both treatment groups (8%) [table III][35] The biopsy-confirmed acute rejections experienced by patients receiving basiliximab were generally less severe than those experienced by RATG recipients; 3 of 4 rejection episodes in those treated with basiliximab were classified as mild (Banff grade I), while 3 of 4 rejection episodes in those treated with RATG were classified as moderate (Banff grade II).[35] There were no significant differences in the rates of graft and patient survival or treatment failure at 12 months between the basiliximab and RATG treatment groups (table III).[35] The incidence of DGF (defined as the need for postoperative dialysis and/or a serum creatinine level >250 mmol/L at day 10 after transplantation) was numerically lower in patients receiving basiliximab than in those receiving RATG (18% vs 22%); however, the difference was not significant.[35] Creatinine clearance in basiliximab recipients was significantly higher than in patients receiving RATG at weeks 4 (63.8 vs 53.9 mL/min; p < 0.01) and 8 (62.6 vs 56.6 mL/min; p < 0.05).[35]

The preliminary (9.8-month) results of a larger randomised, multicentre study (blinding not stated; presented as an abstract) suggest that RATG in combination with MMF-based triple-immunotherapy significantly decreased the incidence of acute rejection episodes (p = 0.013) and treatment failure (p = 0.01) compared with basiliximab in renal transplant recipients at high risk of acute rejection (table III).[36] This study was discontinued early because RATG resulted in fewer renal transplant rejection episodes than basiliximab.[69]

Muromonab CD3

Three retrospective, single-centre studies (n > 100) have compared the efficacy of induction therapy with basiliximab with that of muromonab CD3 in combination with cyclosporin microemulsion or tacrolimus plus corticosteroids and MMF.[3840] In two of these trials, the initiation of cyclosporin microemulsion or tacrolimus was delayed in muromonab CD3 recipients;[38,39] details of the baseline immunosuppression regimen were not reported in the third trial.[40] Patients treated with muromonab CD3 received 5 mg/day for 5–10 days;[38,39] in one trial, the dosage regimens for muromonab CD3 and basiliximab were not reported.[40] The incidence of acute rejection episodes was similar for basiliximab and muromonab CD3 at 6 months in one study (10% vs 16%) [n = 271; available as an abstract];[40] however, two other fully published studies (total n = 242) found that the incidence of acute rejection episodes was significantly lower in basiliximab recipients than in those treated with muromonab CD3 at 100 days (15% vs 38%; p = 0.01)[38] or mean 26 months (16% vs 30%; p = 0.01).[39] Although there were no significant between-treatment differences in graft and patient survival at 100 days,[38] 6 months[40] or 1 year,[38] the 2-year graft survival rate was significantly greater with basiliximab than with muromonab CD3 in one study (87% vs 76%; p = 0.03); patient survival not reported.[39]

4.1.3 Comparison with Daclizumab

Preliminary data are available from a small (n = 23), randomised, nonblind trial in which renal transplant recipients received basiliximab or daclizumab (1 mg/kg within 2 hours prior to surgery and four subsequent doses fortnightly) in combination with MMF, cyclosporin (formulation not specified) and corticosteroids; however, the small size of this study limits the conclusions that can be drawn from it.[37] After a mean 10 months’ follow-up, there were no significant differences in the incidence of biopsy-confirmed acute rejection (1/10 vs 1/13), time to first rejection episode (8 days vs 6 weeks) and graft or patient survival (100% for both treatment groups).[37]

The meta-analysis by Adu et al.[66] also evaluated the efficacy of daclizumab compared with placebo. This meta-analysis suggested that daclizumab reduced acute rejection compared with placebo (25.5% vs 41.2%; p < 0.0001) to an extent similar to that achieved by basiliximab (25.9% vs 38.1%; p < 0.0001).[66]

4.1.4 Corticosteroid- and Calcineurin Inhibitor-Sparing Regimens

Corticosteroids and calcineurin inhibitors may contribute to long-term metabolic deterioration and loss of graft function.[70] Immunosuppressive treatment regimens aimed at sparing corticosteroids or calcineurin inhibitors present attractive options for reducing metabolic complications and improving long-term graft survival in transplant recipients.[70] A number of prospective studies (n > 74) have evaluated the use of basiliximab in corticosteroid-[4749] and calcineurin inhibitor-sparing[46] regimens. The results of these are presented in table IV.
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Table IV

Efficacy of basiliximab (BAS) in trials of corticosteroid- and calcineurin inhibitor-sparing regimens in patients (pts) undergoing renal transplantation

A randomised, nonblind, multicentre trial in adult renal transplant recipients demonstrated that an immunosuppression regimen consisting of basiliximab, cyclosporin microemulsion, MMF and rapid and early corticosteroid withdrawal resulted in similar incidences of biopsy-confirmed acute rejection, and graft and patient survival as a similar regimen with standard corticosteroid therapy (table IV).[47] Renal transplant recipients were randomised to a standard corticosteroid-taper regimen (n = 43) or to a rapid corticosteroid-withdrawal regimen (one dose preoperatively and four doses postoperatively with complete discontinuation of corticosteroid administration on day 5; n = 40) [see table IV for dosage details].[47] It should be noted that this trial was not powered to demonstrate equivalence between the two treatment groups.[47] The incidences of biopsy-confirmed acute rejection episodes at 6 and 12 months were similar in those randomised to the corticosteroid withdrawal or standard corticosteroid regimen treatment group (table IV).[47] Two patients receiving standard corticosteroid treatment required antibody therapy after acute rejection; however, no patients receiving the corticosteroid-withdrawal regimen required antibody therapy (no significant difference).[47] The severity of acute rejections and renal function were also reported as similar in the two treatment groups. The median time to acute rejection was numerically shorter for patients receiving the corticosteroid-withdrawal regimen than for those receiving the standard regimen (31 vs 65 days; statistical analysis not reported).[47] Patient and graft survival was 100% for the corticosteroid-withdrawal treatment group, and one patient receiving standard corticosteroid therapy died with a functioning graft (timepoint not stated).[47]

Two comparative studies, both published in abstract form, reported the effect of eliminating corticosteroids from the immunosuppressive regimen (table IV).[48,49] In the large, randomised study, patients received basiliximab and tacrolimus in combination with a corticosteroid-free regimen in which maintenance doses of corticosteroids were eliminated (n = 152), tacrolimus and MMF plus a similar corticosteroid-free regimen (n = 151) or tacrolimus and MMF plus standard corticosteroid therapy (control patients) [n = 147].[48] The incidence of biopsy-confirmed acute rejection was significantly higher in patients receiving the corticosteroid-free treatment regimens than in the control patients; however, the efficacy of basiliximab and tacrolimus was similar to that of tacrolimus and MMF (table IV).[48] The incidence of corticosteroid-resistant acute rejection (2.0–5.3%) and rates of graft and patient survival (table IV) were similar in all treatment groups.[48] Renal function (assessed by serum creatinine levels and calculated creatinine clearance) was also similar across all treatment groups at 6 months.[48]

A corticosteroid-free regimen comprising basiliximab, cyclosporin microemulsion and MMF or sirolimus (n = 42) was as effective as basiliximab, cyclosporin microemulsion and MMF or sirolimus plus standard corticosteroid therapy (n = 32) [dosages not reported].[49] The incidence of acute rejection 2 years after transplantation was similar for patients receiving a corticosteroid-free or a standard corticosteroid regimen (14% vs 12%).[49] There was also no significant between-group difference in renal function (assessed by serum creatinine levels and creatinine clearance) 1 year after surgery.[49] Rates of graft and patient survival at 2 years were also similar for both treatment groups (table IV).

Basiliximab in combination with a calcineurin inhibitor-sparing regimen was significantly more effective in preventing biopsy-confirmed acute rejection in renal transplant recipients than basiliximab plus a standard cyclosporin microemulsion regimen or muromonab CD3 or ATG plus a calcineurin inhibitor-sparing regimen (table IV).[46] Recipients of cadaveric renal transplants were assigned to one of three treatment groups according to their risk of DGF.[46] Patients at high risk of DGF received therapy with basiliximab, sirolimus, corticosteroids plus low-dose cyclosporin microemulsion (defined as a cyclosporin microemulsion dosage required to achieve drug exposure that was 30% of that achieved in the other treatment groups receiving the full dosage) delayed until after the resolution of DGF (defined as a fall in serum creatinine to ≤2.5 mg/dL) [n = 43], or muromonab CD3 or ATG and corticosteroids plus delayed cyclosporin microemulsion (n = 18).[46] Patients at low risk of DGF received basiliximab, corticosteroids and immediate cyclosporin microemulsion (n = 21).[46] There was no significant difference in the rate of patient or graft survival between the three treatment groups (table IV). The mean number of cyclosporin microemulsion-free days was significantly higher in those receiving basiliximab plus sirolimus than in those receiving basiliximab plus immediate cyclosporin microemulsion (42 vs 0 days; p = 0.005) or muromonab CD3 or ATG plus delayed cyclosporin microemulsion (9 days; p = 0.04).[46] Over the 12 months of follow-up, the mean dosage of cyclosporin microemulsion and corticosteroids was also significantly lower for those patients receiving basiliximab plus sirolimus than for those in the other two treatment groups (p < 0.001 for both comparisons).[46]

4.1.5 Elderly Patients

Limited data from a retrospective study in renal transplant recipients aged ≥60 years showed that there was no significant difference in the incidence of acute organ rejection in elderly patients treated with basiliximab induction therapy (n = 33) or muromonab CD3 (n = 18), both in combination with triple-immunotherapy including cyclosporin microemulsion or tacrolimus, plus MMF and corticosteroids (4/33 vs 5/18).[41] It should be noted that patients receiving basiliximab received low-dose cyclosporin microemulsion or tacrolimus initiated immediately after transplantation, and patients receiving muromonab CD3 recipients received delayed cyclosporin microemulsion or tacrolimus.[41]

4.1.6 Patients with Type 1 or Type 2 Diabetes Mellitus

The effect of basiliximab in a subgroup of patients with either type 1 or type 2 diabetes mellitus (n = 150) has been assessed in a pooled analysis[71] of data from two placebo-controlled clinical trials (section 4.1.1).[28,29] In the pooled trials, 80 patients with diabetes mellitus received basiliximab and 70 received placebo.[71]

Basiliximab reduced the proportion of patients with diabetes mellitus experiencing first acute rejection or biopsy-confirmed rejection by 41% and 44% (p < 0.01 for both).[71] Basiliximab was also associated with a significantly lower rate of treatment failure than placebo (35% vs 61%; p = 0.001).[71] Additionally, the rate of graft survival was significantly higher in patients receiving basiliximab than in placebo recipients (96% vs 86%; p = 0.022).[71]

4.2 Paediatric Patients

4.2.1 Comparisons with No Induction Therapy

Two small (n < 100), retrospective trials compared the efficacy of induction therapy with basiliximab in combination with dual-immunotherapy (cyclosporin microemulsion or tacrolimus plus corticosteroids) with dual-immunotherapy alone (control patients) in paediatric renal transplant recipients.[42,43] Mean age was approximately 15 years in one trial[42] and approximately 7 years in the other.[43] Basiliximab was administered on the day of transplantation and 4 days later.[42,43] The dosage of basiliximab in one trial was 12 mg/m2/dose.[42] In the other trial, patients weighing <35kg were given basiliximab 10 mg/dose and those >35kg were given basiliximab 20 mg/dose.[43] There was no significant difference between the treatment groups in the incidence of acute organ rejection 12 months after transplantation (7/48 vs 4/26[43] and 6/24 vs 3/8).[42] Graft survival at 12 months was also similar for patients receiving basiliximab or no induction therapy (45/48 vs 24/26[43] and 21/24 vs 6/8),[42] and patient survival 1 year after transplantation was 100% for both treatment groups in both clinical trials.[42,43]

A placebo-controlled trial in paediatric renal transplant recipients is currently underway, with results expected to be announced in 2005.[52]

4.2.2 Comparisons with ATG or Antilymphocyte Globulin (ALG)

A retrospective, single-centre study of 84 paediatric renal transplant recipients treated with basiliximab induction therapy (20mg for patients weighing ≥35kg or 10mg for patients <35kg on days 0 and 4) in combination with dual-immunotherapy (cyclosporin microemulsion and corticosteroids) [patient mean age 10 years] or ALG (0.2 mg/kg on days 0–3) in combination with triple-immunotherapy (cyclosporin microemulsion and corticosteroids plus azathioprine) [patient mean age 12 years] suggested similar efficacy for these two treatment regimens in paediatric patients.[44] The incidence of acute organ rejection episodes at 6 months was not significantly different in patients treated with basiliximab or ALG (19/42 vs 26/42).[44] The rate of graft survival at 12 months and 2 years was also not significantly different in the two treatment groups (39/42 vs 36/42 for both timepoints), and one patient in each treatment group died in the 6 months follow-up after transplantation.[44] Renal function (as assessed by the absolute glomerular filtration rate) at 6 months after transplantation was also similar in patients treated with basiliximab or ALG.[44]

The efficacy of basiliximab in combination with immediate cyclosporin therapy has also been reported in comparison with ATG/ALG plus delayed cyclosporin therapy in a retrospective, single-centre clinical trial in paediatric renal transplant recipients (ages not reported).[45] Basiliximab (n = 23) was given at a dose of 20mg for patients weighing >40kg and 10mg for patients <40kg immediately before transplantation and on day 4. The exact dosage of ATG/ALG (n = 27) was not reported. Baseline immunotherapy included cyclosporin (formulation not specified), azathioprine and corticosteroids in both treatment groups.[45] Treatment with basiliximab resulted in a numerically lower incidence of biopsy-confirmed acute organ rejections in the first 6 months after transplantation (2/23 vs 9/27; statistical analysis not reported).[45] However, graft survival was similar for both treatment groups at 12 months (22/23 vs 26/27) and 3 years (21/23 vs 25/27).[45]

5. Tolerability

Overall, basiliximab induction therapy appears to be generally well tolerated. Tolerability data at 6 or 12 months after transplantation are available from the comparative trials reviewed in section 4,[2832,3436,3840,4447,71] pooled data from four placebo-controlled trials[28,29,31,32] reported in the prescribing information[12,15] and two meta-analyses.[66,67] Long-term data on the incidence of malignancies and infection are available from a pooled analysis of two 4-year nonblind extension phases of two 12-month placebo-controlled trials, reported in the European prescribing information,[15] and results at 3 years after transplantation have been reported from a small, randomised study.[33]

5.1 Adult Patients

5.1.1 General Adverse Event Profile

Basiliximab did not increase the incidence of adverse events observed in adult renal transplant recipients as a consequence of their underlying disease or the concomitant administration of other immunosuppressive agents when compared with placebo.[2832] First-dose reactions, cytokine release syndrome and local adverse events related to the IV bolus injection or infusion of basiliximab were not reported in prospective clinical trials.[28,29,31,32,34,37,46]

In placebo-controlled studies, the total incidence of all adverse events was similar in basiliximab and placebo recipients (71.2–100% vs 68.2–100%);[28,3032] there was also no significant difference for the incidence of adverse events considered to be possibly or probably related to treatment (7.1–27.2% vs 7.6–35.3%)[28,31,32] between those receiving basiliximab and placebo recipients. Adverse events were reported as generally mild to moderate,[28,31] and the percentage of patients experiencing severe adverse events was also similar in the basiliximab and placebo treatment groups (54% vs 61%[28] and 35.6% vs 34.4%;[32] Lawen et al.[32] reported serious adverse events excluding serious infection). In one study,[28] induction therapy with basiliximab was associated with a significantly lower incidence of thrombotic events than that with placebo (6% vs 21%; p < 0.05).

The meta-analysis by Keown et al.[67] (see section 4.1.1 for further details) reported that there was no significant difference in the incidence of adverse events between basiliximab and placebo recipients (96.3% vs 95.5%). Gastrointestinal disorders (e.g. constipation, nausea, abdominal pain, vomiting, diarrhoea and dyspepsia) were the most common adverse events in the basiliximab and placebo treatment groups (69% vs 67%).[12] Other adverse events occurring in ≥10% of patients receiving basiliximab (specific incidences not reported) included pain, peripheral oedema, fever, dyspnoea, headache, tremor, insomnia, anaemia, acne, surgical wound complications, urinary tract infection, upper respiratory tract infection, viral infection, and metabolic and electrolyte disturbances.[12]

The overall profile of laboratory parameters and vital signs (e.g. blood pressure, hepatic function, metabolic function, haematological parameters) was similar for the basiliximab and placebo treatment groups.[28,29,31,32]

In randomised, comparative, triple-immunotherapy trials, the incidence of adverse events with basiliximab was similar to that with ATG (both 100%)[34] or RATG (90.2% vs 94.0%[35]. Moreover, there was no significant difference in the incidence of severe adverse events between the basiliximab and ATG (61% vs 66%)[34] or RATG treatment groups (49.0% vs 50.0%).[35] Adverse events considered to be related to the study drug occurred in 11% of basiliximab recipients and 42% of ATG recipients (statistical analysis not reported).[34] Twelve and 43 adverse events thought to be related to treatment occurred in 8 basiliximab and 24 RATG recipients, respectively (p = 0.0006).[35] In the study comparing basiliximab with RATG in patients at high risk of acute rejection the incidences of fever and leukopenia were significantly lower in basiliximab recipients than in those receiving RATG (p < 0.001 and p < 0.03, respectively) [figure 2][35]
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Fig. 2

Adverse events thought to be related to the study drug after induction therapy with an intravenous bolus injection of basiliximab 20mg on days 0 and 4 (n = 51) or an intravenous infusion of rabbit antithymocyte globulin (RATG) 1.0–1.5 mg/kg (n = 50) in addition to standard immunotherapy with mycophenolate mofetil, cyclosporin microemulsion and corticosteroids in adult renal transplant recipients.[35] * p < 0.03, ** p < 0.001 vs RATG.

In high-risk patients, there was no significant difference between basiliximab and RATG for laboratory parameters (including cholesterol levels) or blood pressure; however, patients receiving RATG had significantly lower lymphocyte counts than basiliximab recipients after the first week (p = 0.001).[35]

The tolerability of basiliximab compared with that of the monoclonal antibodies muromonab CD3 and daclizumab has not been reported.

There was no significant difference in the incidence of serious adverse events between renal transplant recipients receiving basiliximab in combination with a corticosteroid-withdrawal regimen and those receiving induction therapy with basiliximab plus standard corticosteroid therapy (28% vs 23%).[47] Similarly, the overall tolerability of basiliximab in combination with a corticosteroid-free regimen plus tacrolimus was similar to that of a corticosteroid-free regimen plus tacrolimus and MMF and similar to that of a standard corticosteroid regimen plus tacrolimus and MMF; however, significant differences were reported for the incidence of anaemia (14.5%, 12.6% and 24.5%), diarrhoea (5.9%, 17.9% and 12.9%), leukopenia (5.9%, 18.5% and 7.5%) and tremor (4.6%, 7.3% and 0.7%) [p values not reported].[48]

Basiliximab was better tolerated than muromonab CD3 in elderly patients,[41] and its tolerability in patients with either type 1 or type 2 diabetes mellitus was similar to that in the general patient population.[71]

Although no instances of hypersensitivity reactions or anaphylaxis were reported in the clinical trials reviewed in section 4, rare (<1 per 1000 patients) cases of severe acute (onset within 24 hours) hypersensitivity reactions, including anaphylaxis, have been reported during postmarketing experience after an initial exposure to basiliximab or after a subsequent course of therapy after several months.[12,15] Hypersensitivity reactions may include hypotension, tachycardia, cardiac failure, dyspnoea, wheezing, bronchospasm, pulmonary oedema, respiratory failure, urticaria, rash, pruritus, sneezing and capillary leak syndrome.[12,15] The prescribing information for basiliximab suggests that if a severe hypersensitivity reaction occurs, treatment with basiliximab should be permanently discontinued and the reaction treated (section 7).[12,15] 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 (section 7).[12]

5.1.2 Infection and Malignancy

In common with other immunosuppressants, basiliximab recipients have an increased risk of infections (bacterial, viral and fungal). In placebo-controlled trials, the majority of patients had multiple opportunistic infections during the first 6 months after transplantation, although the incidence of these infections was similar in basiliximab and placebo recipients (54.9–84.7% vs 52.6–86.6%).[2832] Urinary tract infections were the most common infections reported in basiliximab or placebo recipients (33% vs 31%[28] and 58.4% vs 60.8%[29]. The incidence of cytomegalovirus (CMV) infection, a good indicator of the level of immunosuppression, occurred in a similar proportion of basiliximab and placebo recipients in dual- (6.9% vs 9.2%[28] and 20.5% vs 26.9%[29] and azathioprine-based (17.3% vs 14.5%)[31] and MMF-based (13.6% vs 18.8%)[32] triple-immunotherapy trials.

Basiliximab recipients had a significantly lower incidence of infection with herpes simplex virus than those receiving placebo in a dual-immunotherapy trial (2.9% vs 9.2%; p < 0.05).[28] This was thought to be due to the fact that placebo recipients received greater dosages of corticosteroids or muromonab CD3 to treat the higher rate of acute rejection episodes.[28]

In the meta-analysis by Adu et al.[66] (see section 4.1.1 for further details), induction therapy with monoclonal IL-2Rα antibodies (including basiliximab) had no significant effect on the incidence of overall infection or on CMV infection (timepoint not reported) compared with placebo. Similarly, the meta-analysis by Keown et al.[67] found no significant difference between basiliximab or placebo recipients in the incidence of overall infection (74.8% vs 75.5%).

There was no significant difference in the incidence of infection between basiliximab and ATG (76% vs 77%)[34] or between basiliximab and RATG (64.7% vs 86.0%).[35] The most common infections reported in one trial were respiratory tract or urinary tract infections.[35] Basiliximab had a similar incidence of CMV infection as ATG (19% vs 17%).[34] In one trial, the incidence of CMV infection was similar for basiliximab and RATG (13.2% vs 7.1%);[36] however, in the other trial, the incidence was significantly lower with basiliximab than with RATG (11.8% vs 38.0%; p = 0.005).[35]

The incidence of serious infections was also not significantly different in renal transplant recipients receiving basiliximab in combination with a corticosteroid-withdrawal regimen and in those receiving induction therapy with basiliximab and standard corticosteroid therapy (13% vs 5%).[47]

Post-transplant lymphoproliferative disorders (PTLD) and other malignancies were rare in the basiliximab and placebo groups in placebo-controlled trials.[2832] PTLD occurred in 0%–0.6% of patients receiving basiliximab or placebo in the 6 or 12 months following renal transplantation.[2832] The frequency of malignancy (including basal cell carcinoma, Kaposi sarcoma, cervical epidermoid carcinoma, breast carcinoma, squamous cell carcinoma, hypernephroma, adenocarcinoma, melanoma, cerebral glioma or multiple myeloma) in the 6 or 12 months following transplantation was similar in patients receiving basiliximab or placebo (0–1.8% vs 0–3.5%).[2832]

In a pooled analysis of two 4-year nonblind extension phases of two 12-month placebo-controlled trials, the incidence of malignancies and PTLD was the same for patients receiving basiliximab or placebo (7% for both treatment groups).[15] Similarly, 3 years after renal transplantation, there was no significant difference in the incidence of malignancies or infection, including CMV infection, between patients receiving induction therapy with basiliximab and those receiving no induction therapy in a small, randomised study.[33]

In addition, in the meta-analysis by Adu et al.,[66] basiliximab did not increase the risk of lymphoma or other malignancies compared with placebo 12 months after transplantation.

There was no significant difference in the incidence of malignancy between those receiving basiliximab and ATG (1% vs 5%), and no cases of PTLD were reported in either treatment group after 12 months.[34] In addition, in a fully published comparative trial with RATG, no patients randomised to receive basiliximab or RATG developed malignancies or PTLD 6 or 12 months after transplantation.[35] The preliminary results of a larger randomised, multicentre trial showed there was no significant difference between basiliximab and RATG for the incidence of malignancy (0.7% vs 2.1%) in the 9.8 months following renal transplantation.[36]

5.2 Paediatric Patients

Limited tolerability data are available from the retrospective, comparative trials examining the use of basiliximab in paediatric patients (section 4.2). The incidence of CMV infection was numerically lower in paediatric patients receiving induction therapy with basiliximab than in those receiving ALG (4/42 vs 8/42), but the difference was not significant.[44] However, the difference in the incidence of CMV infection between the basiliximab and ALG treatment groups became significant when only renal transplant recipients seropositive for CMV antibodies were considered (0/16 vs 8/15; p < 0.01).[44]

Similarly, in another trial, treatment with basiliximab resulted in a numerically lower rate of reactivation or de novo infection with human herpes virus type 6 (5/23 vs 15/27) or Epstein Barr virus (5/23 vs 14/27) and a numerically lower incidence of thrombocytopenia (3/23 vs 15/27) and unexplained fever (0/23 vs 14/27) than ATG/ALG therapy (statistical analysis not reported).[45]

6. Pharmacoeconomic Considerations

6.1 Comparisons with Placebo

Three prospective economic analyses (table V) have been performed on randomised, placebo-controlled clinical trials (reviewed in section 4.1.1).[7274]
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Table V

Economic evaluations of intravenous basiliximab (BAS) 20mg vs placebo (PL) administered within 2 hours prior to renal transplantation and 4 days after transplantation in combination with dual-a or azathioprine-based triple- immunotherapyb in renal transplant recipients. Evaluations used an institutional perspective and prospective efficacy data from double-blind, randomised, PL-controlled clinical trials. Efficacy assessments were made at the end of the study period (6 or 12 months). Costs were reported as per patient with concomitant immunotherapy. Mean costs were reported unless otherwise indicated

All three studies used prospective clinical data and were conducted from an institutional perspective. There were no statistically significant differences in the various or total costs of treatment between basiliximab recipients and those receiving placebo at 6[74] and 12 months (table V).[72,73] One study reported a 24% probability that basiliximab reduced costs compared with placebo (bootstrap analysis).[72] In another study, sensitivity analyses showed the differences in costs were consistently lower in the basiliximab-treated group when hospitalisation cost per day and physician consulting fees were increased or decreased by 25% and 50%.[73]

Induction therapy with basiliximab demonstrated significant clinical efficacy in renal transplant recipients without increasing overall treatment costs relative to placebo.[7274] Chilcott et al.[72] reported the cost per suspected rejection episode avoided with basiliximab treatment as $US9823 (year of cost 1996), and that six patients needed to be treated with basiliximab for one additional patient to avoid a suspected rejection episode in the 12 months following transplantation. Similarly, Walters et al.[74] reported the cost per treatment failure avoided as $US4669 (year of cost 1996), and that eight patients needed to be treated with basiliximab rather than placebo for one additional patient to have no treatment failure in the 6 months following transplantation.

In addition to the above studies, a Canadian cost-evaluation model based on clinical data from the placebo-controlled clinical trial by Nashan et al.[29] suggested that basiliximab produces an estimated total cost saving of 4554 Canadian dollars ($Can) per patient (excluding the cost of basiliximab; 1999 currency year) 12 months after renal transplantation, a net saving of $Can1554 when an estimated cost of basiliximab of $Can3000 per patient was included.[75] These savings have been attributed to reduced costs of initial hospitalisation and acute rejection, reductions in the incidence of graft loss, with an accompanying reduction in costs of return to dialysis and repeat transplantation, and to the reduction in the rate of follow-up hospitalisations (excluding acute rejection).[75] Sensitivity analysis showed that the cost savings with basiliximab increased as initial hospitalisation time decreased.[75] The model was conservatively extended to predict the costs of treatment 5 years after transplantation resulting in a cost saving of $Can11 908 per basiliximab recipient, a net saving of $Can8908 after the estimated cost of basiliximab was included.[75]

Additionally, a Japanese cost evaluation model[76] using clinical data from two placebo-controlled trials[28,29] suggested basiliximab produces an estimated total cost saving of 315 807 yen per patient (2000 currency year) 12 months after renal transplantation when the cost of basiliximab is not included. This cost saving was attributed to a reduction in the costs of treatment for acute rejection and dialysis.[76] A sensitivity analysis suggested that the economic model was effective.[76]

6.2 Comparisons with Other Immunosuppressive Agents

Preliminary results from a cost-utility analysis conducted from a societal perspective using an economic model suggest that the total cost of treatment (including the cost of initial hospitalisation, acute rejection treatment, graft failure and dialysis, maintaining a functional graft and induction agents) in basiliximab recipients over a 5-year period following transplantation ($US154 806) was similar to that in daclizumab recipients ($US155 712) and numerically less than that in recipients of muromonab CD3 ($US181 113) or standard therapy (regimen not reported; $US166 124).[77] Currency year, drug dosages and statistical analysis were not reported in the abstract. The cost per additional quality-adjusted life-year (QALY) was similar with basiliximab and daclizumab, but numerically higher with muromonab CD3 and standard therapy ($US51 182, $US48 665, $US60 391 and $US56 646, respectively).[77]

A French cost-minimisation study conducted from an institutional perspective using clinical trial data and costs of medications, hospitalisation, dialysis and consultations found that, although the cost of induction therapy with basiliximab was numerically higher than the cost of RATG (euro2964 vs euro2298; currency year and statistical analysis not reported), the total cost of initial hospitalisation was significantly lower in patients receiving basiliximab than in those receiving RATG (euro10 907 vs euro11 967; p < 0.02).[78]

A further economic analysis evaluated the costs of treatment in renal transplant recipients treated with basiliximab or ATG.[79] This study reported costs in 1997 US dollars. Total treatment costs (cost of initial hospitalisation, physician fees, drug acquisition costs, outpatient treatment and the cost of rehospitalisation) were lower for renal transplant recipients treated with basiliximab and triple-immunotherapy (cyclosporin microemulsion and corticosteroids plus MMF) than for those treated with ATG plus corticosteroids, MMF and delayed cyclosporin microemulsion ($US45 857 vs $US54 729 [difference $US8872; 95%CI $US1169 to $US16 573]).[79] Study drug costs were lower in those receiving basiliximab than in those treated with ATG ($US2378 vs $US8670 [difference $US6292; 95%CI $US5165 to $US7419]).[79] However, there was no significant difference between the two treatment groups in patient-assessed health-related quality of life within 12 months of transplantation (the 1-year QALY score was 81.5 and 81.1, respectively, for patients receiving ATG and basiliximab [a score of 100 represents 100% survival at perfect health]).[79]

7. Dosage and Administration

Basiliximab is indicated for the prophylaxis of acute organ rejection, as part of an immunosuppressive regimen that includes cyclosporin microemulsion and corticosteroids, in patients undergoing renal transplantation in the US and Europe.[12,15] The recommended dosage of basiliximab in adult and paediatric (≥35kg bodyweight) renal transplant recipients is 20mg administered within 2 hours prior to transplantation surgery and a second dose 4 days after transplantation.[12,15] In paediatric patients weighing <35kg, a similar regimen is recommended with two doses of 10mg each.[12,15] Reconstituted basiliximab can be administered by IV bolus injection or can be diluted to a volume of 50mL with normal saline or 5% dextrose and administered by IV infusion over 20–30 minutes.[12,15]

No dosage adjustments are necessary when basiliximab is combined with triple-immunotherapy regimens including cyclosporin microemulsion, corticosteroids plus azathioprine or MMF, or when administered to elderly patients; however, caution must be used when administering immunosuppressive drugs to elderly patients.[12,15] Although there are no formal recommendations, it has been suggested that increased drug level monitoring and adjustments to the dosage of the calcineurin inhibitors may be necessary for transplant recipients receiving basiliximab in order to reduce the risk of adverse events or an acute rejection episode (section 3.3).[26,27]

Basiliximab is contraindicated in patients with a known hypersensitivity to it or its components.[12,15] If a hypersensitivity reaction occurs, treatment with basiliximab should be permanently discontinued and the reaction treated appropriately.[12] The US prescribing information suggests that patients previously treated with basiliximab only be re-exposed to the drug with extreme caution.[12]

Although the incidence of PTLD and infections were not increased in basiliximab recipients compared with those receiving comparator agents (section 5.1.2), patients receiving immunotherapy are at increased risk of developing the complications and should be monitored accordingly.[12]

8. Place of Basiliximab Induction Therapy in the Prevention of Acute Rejection in Renal Transplant Recipients

Despite improvements in renal transplantation and expansion of the options for immunosuppressive agents (including cyclosporin microemulsion, tacrolimus, corticosteroids, azathioprine and MMF), acute rejection remains an important risk factor for the development of graft dysfunction and chronic rejection, and is associated with poor long-term graft survival.[80] Additionally, the long-term use of calcineurin inhibitors has been associated with nephrotoxicity and hypertension, and long-term use of corticosteroids has been associated with hyperlipidaemia, weight gain, post-transplantation diabetes mellitus and an increased risk of cardiovascular disease.[81]

The goals of immunotherapy are to prevent acute rejection and maximise graft and patient survival, while minimising complications such as infection or malignancy.[1,2] Immunosuppressive regimens (drug combinations used, dosage and timing of administration) vary among transplant centres.[1] However, standard immunotherapy in renal transplantation consists of baseline therapy to prevent rejection and short courses of high dose corticosteroids or monoclonal or polyclonal antibodies for the treatment of acute rejection episodes.[82] Triple-immunotherapy with cyclosporin, corticosteroids and azathioprine was the most frequently used baseline immunotherapy during the 1990s;[82,83] however, MMF and tacrolimus are now also recommended for use in baseline immunotherapy regimens.[83] Induction therapy consists of short-term immunosuppression at the initial exposure of the recipient’s immune system to foreign antigens present on the transplanted organ.[4,10] It is regarded as an optional therapy to reduce the number and severity of acute rejections.[83] Guidelines produced by the European Renal Association and European Dialysis and Transplant Association do not recommend one agent over another.[83] They state that the lymphocyte-depleting agents ALG, ATG or muromonab CD3 have similar efficacy and do not consistently improve graft survival 3 years after renal transplantation.[83] However, renal transplant recipients with delayed graft function, or with low or high panel reactive antibodies directed against HLA, may benefit from these agents.[83] These lymphocyte-depleting agents have resulted in a number of serious adverse events and so now are mainly used in the treatment of corticosteroid-resistant rejection.[1] The European guidelines also state that basiliximab and daclizumab have been proven to be safe and effective in renal transplant recipients.[83]

Basiliximab was developed as an induction agent specific for activated T lymphocytes. Clinical trials have shown that induction therapy with basiliximab is effective (section 4) and generally well tolerated (section 5) in combination with standard dual- or triple-immunotherapy and in corticosteroid- or calcineurin inhibitor-sparing regimens.

The long t½ of basiliximab allows for a convenient two-dose administration regimen (sections 3 and 7). Although the pharmacokinetic profile of basiliximab is altered when it is administered in combination with azathioprine- or MMF-based triple-immunotherapy (section 3.3), no adjustments to the basiliximab dosage are necessary (section 7). Two retrospective analyses have suggested that there may be significant drug interactions between basiliximab and the calcineurin inhibitors cyclosporin (formulation not specified) and tacrolimus.[26,27] Although there are no formal recommendations, increased drug level monitoring and adjustments to the dosage of the calcineurin inhibitor have been suggested for transplant recipients receiving basiliximab in order to reduce the risk of adverse events or the risk of an acute rejection episode (section 3.3).

The efficacy of induction therapy with basiliximab when used in combination with standard therapy with cyclosporin microemulsion and corticosteroids, with or without azathioprine or MMF, has been investigated in five large, well designed, double-blind, randomised, placebo-controlled trials in adult renal transplant recipients (section 4.1.1).[2832] Basiliximab significantly reduced acute rejection in the 6 or 12 months following transplantation compared with placebo in adult renal transplant recipients receiving either dual-[28,29] or azathioprine-based triple-immunotherapy (section 4.1.1).[30,31] The incidence of acute rejection was not significantly different for patients receiving basiliximab or placebo in combination with MMF-based triple-immunotherapy (section 4.1.1).[32]

The histological severity of biopsy-confirmed acute rejection episodes were generally similar with basiliximab or placebo (section 4.1.1).[28,29,31] However, patients treated with basiliximab required lower dosages of corticosteroids at weeks 2 and 4 after transplantation[28,29,31] and experienced fewer corticosteroid-resistant rejection episodes requiring treatment with other immunosuppressive agents than those receiving placebo (section 4.1.1).[28,29] Induction therapy with basiliximab resulted in a similar[29,32] or more rapid[28] improvement in renal graft function. Patient and graft survival at 6 or 12 months was similar for both treatment groups.[2832] In a pooled analysis[52] of two extension phases of two placebo-controlled trials,[28,29] significantly more basiliximab recipients were free from the combined endpoint of death, graft loss or acute rejection than those receiving placebo 3 years after transplantation surgery (p = 0.025); however, there was no significant difference between the treatment groups for this endpoint 5 years after transplantation (section 4.1.1). The benefit of treatment with basiliximab in combination with cyclosporin microemulsion and corticosteroids was found in both cadaveric- and living-donor graft recipients (section 4.1.1).[68]

Patients receiving basiliximab did not experience cytokine release syndrome. In placebo-controlled trials, adult patients receiving basiliximab experienced a broadly similar number and type of adverse events as those receiving placebo (section 5.1.1). The most common adverse events occurring with basiliximab therapy were gastrointestinal disorders (e.g. constipation, nausea, abdominal pain, vomiting, diarrhoea and dyspepsia). Rare hypersensitivity reactions have been recorded in patients receiving a first or second course of basiliximab (section 5.1.1). Importantly, basiliximab does not increase the incidence of infections, including CMV infections over 6–12 months compared with placebo (section 5.1.2), and is minimally immunogenic (section 2.4). Urinary tract infections were the most common infections reported after treatment with basiliximab or placebo. The incidence of malignancies and post-transplant lymphoproliferative disorders was similar in those receiving basiliximab or placebo 6–12 months or 5 years after transplantation (section 5.1.2).

Although data are limited, results from retrospective analyses in paediatric (section 4.2) or elderly (section 4.1.5) renal transplant recipients have suggested that basiliximab is effective and well tolerated in these patient groups.[4143] Further well designed trials in these patient populations are currently underway. A pooled analysis has shown that basiliximab significantly reduced acute rejection and increased graft survival in renal transplant recipients with type 1 or type 2 diabetes mellitus (section 4.1.6).[71]

In comparative trials, basiliximab was generally as effective as ATG,[34] RATG[35] or daclizumab[37] in reducing acute rejection episodes in adult renal transplant recipients (section 4.1.2) and as effective as ATG or ALG in paediatric renal transplant recipients (section 4.2.2);[44,45] however, the incidence of acute rejection episodes was significantly lower in basiliximab recipients than in those treated with muromonab CD3 at 100 days[38] or a mean 26 months (section 4.1.2).[39] Conversely, limited data from a single clinical trial suggest that RATG is more effective than basiliximab in preventing acute rejection in adult renal transplant recipients at high risk of acute rejection (section 4.1.2).[36] However, this study has been reported only as an abstract and the blinding of the trial and specific dosage details of baseline immunotherapies were not reported.[36]

Basiliximab appears to allow the withdrawal of corticosteroids[47] or the use of corticosteroid-free regimens[48,49] in renal transplant patients (section 4.1.4). Basiliximab in combination with a delayed low-dose cyclosporin microemulsion regimen also resulted in effective immunosuppression (section 4.1.4).[46]

Further well designed, comparative studies would be beneficial to establish the relative efficacy of basiliximab compared with the lymphocyte-depleting induction agents. Trials assessing the efficacy of basiliximab in combination with newer immunosuppressive agents such as sirolimus, everolimus or FTY-720 would also be useful.

Despite similar efficacy, some alternative induction agents to basiliximab appear to have higher costs and tolerability concerns associated with their use. Muromonab CD3, a murine monoclonal antibody against human CD3, has been associated with high immunogenicity and serious adverse events, including the sometimes fatal cytokine release syndrome.[84] ATG has also been associated with serious adverse events, such as anaphylaxis and serum sickness.[4] The incidence of adverse events, infections or malignancy with basiliximab was similar to that with ATG or RATG; however, the incidences of fever and leukopenia were significantly lower in basiliximab recipients than in those receiving RATG (p < 0.001 and p < 0.03) [section 5.1.1].[35]

Limited comparative pharmacoeconomic data are available; however, basiliximab appears to be cost effective compared with placebo (section 6.1). Limited data have also suggested that total costs of treatment in basiliximab recipients were similar to that of daclizumab and less than that of muromonab CD3. Additionally, although the acquisition cost of basiliximab is greater than that of RATG in France, the total cost of initial hospitalisation is reduced after basiliximab therapy compared with RATG (section 6.2). However, further research is required on the long-term economic impact of basiliximab.

Numerous clinical trials have shown that the humanised monoclonal antibody daclizumab, like basiliximab, significantly reduces the incidence of acute rejection and is generally well tolerated in renal transplant recipients.[85] The relative efficacy of basiliximab and daclizumab has not been compared in well controlled trials in adequate numbers of patients. The affinity of basiliximab for the IL-2 receptor is 10-fold higher than that of daclizumab.[2] It is not known whether this difference is clinically important; however, it does not appear to be associated with differences in the incidence of acute rejection.[2] In addition, the dosage regimen of basiliximab (two doses of 20mg administered on the day of transplantation and 4 days later) is much simpler than the recommended dosage of daclizumab (1 mg/kg within 24 hours before surgery and once every 2 weeks thereafter for a total of five doses),[85] as the administration of basiliximab ends 4 days after transplantation, whereas administration of daclizumab continues periodically for up to 60 days after transplantation.

In 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.

Footnotes
1

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