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PubMed2004

Double-blind comparison of hepatitis C histological recurrence Rate in HCV+ Liver transplant recipients given basiliximab + steroids or basiliximab + placebo, in addition to cyclosporine and azathioprine.

BACKGROUND: Hepatitis C virus (HCV) recurrence in HCV+ liver transplant recipients is almost inevitable and may be promoted by immunosuppression. We compared the amount of liver damage with regard to usage of steroids and basiliximab. METHODS: A total of 140 HCV+ adult liver transplant recipients were randomly allocated to basiliximab + steroids or basiliximab + placebo (plus cyclosporine and azathioprine). Primary endpoint: hepatitis C histological recurrence (liver damage as for Ishak grading score >or=8 by biopsy at 12 months); secondary endpoints: treatment failure (death, graft loss, patient withdrawal), biopsy proven acute rejection (BPAR), treated acute rejection (tAR), allograft and patient survival rates at 12 months. RESULTS: Any significant difference has been observed in the 12-month hepatitis C histological recurrence rate (41.2% basiliximab + steroids, 37.5% basiliximab + placebo, P = 0.354). The treatment failure rate was significantly higher in basiliximab + steroids (28.8%) than in basiliximab + placebo (15.6%), P = 0.03; the combination test for the evaluation of the joint hypothesis resulted in a borderline nonsignificant overall result (P = 0.059). BPAR rate was significantly lower in the group treated with steroids (24.3% basiliximab + steroids, 39.4% basiliximab + placebo, P = 0.04), while the tAR rate was similar (29.7% basiliximab + steroids and 37.9% basiliximab + placebo). Any significant differences in 1-year graft and patient survival rates have been observed (72.9% and 84.8% basiliximab+steroids; 81.5% and 89.0% basiliximab + placebo). CONCLUSIONS: Results suggest that steroid-free therapy is associated with a significantly lower treatment failure rate, although histological recurrence rate of hepatitis C is similar in the two groups. This benefit is not offset by an evident increase in graft rejection rate requiring treatment.

Adrenal Cortex Hormones↗
PubMed2003

Tacrolimus-Basiliximab versus Cyclosporine-Basiliximab in renal transplantation "de novo": acute rejection and complications.

BACKGROUND: Optimal immunosuppression is essential to maintain kidney allograft viability but minimizing toxicity is also fundamental. OBJECTIVE: This article compares immunosuppressants, corticosteroids, cyclosporine, tacrolimus, and basiliximab, which are used in the treatment regimens for renal transplantation. The analyses evaluated their effectiveness to prevent acute rejection episodes and to reduce the appearance of other complications, mainly infectious disease complications. METHODS: Ninety-five patients were analysed during the first year after primary renal transplantation. These patients were included in a random way in 3 different groups according to the immunosuppressant drug therapy: Group I (35 patients) received corticosteroids + CsA; Group II (35 patients) received corticosteroids + CsA + Basiliximab; Group III (25 patients) received corticosteroids + Tacrolimus + Basiliximab. RESULTS: Among the 95 patients, 9 presented with an acute rejection episode in Group I. None in Group II, and one in group III. With reference to the infectious disease complications, the incidence of oral herpes was one case in Group I, 4 cases in Group II, and 2 cases in group III. CONCLUSIONS: Treatment with Basiliximab produced a significantly lower incidence of acute rejection cases and an increase in infectious disease complications, such as lip herpes.

Adult↗
PubMed2003

Basiliximab: a review of its use as induction therapy in renal transplantation.

UNLABELLED: 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 cytomegalovirus (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.

Adolescent↗
PubMed2001

Economic analysis of basiliximab in renal transplantation.

BACKGROUND: Basiliximab is a chimeric monoclonal directed against the alpha-chain of the interleukin-2 receptor. International studies have shown that it is highly effective in preventing acute rejection in patients receiving Neoral, and causes no measurable incremental toxicity, but its economic value remains unknown. METHODS: This study employed an economic model to examine the potential economic benefit of basiliximab. Parameter estimates were derived from a randomized, prospective, double-blind study conducted in 21 renal transplant centers in seven countries in which 380 adult primary allograft recipients were randomized within center to receive basiliximab (20 mg i.v.) on days 0 and 4 or placebo in addition to dual immunosuppression with Neoral and steroids. Key clinical events included primary hospitalization, immunosuppressive drug use, patient and graft survival, graft rejection, treatment of rejection, dialysis, and repeat hospitalization. Health resources were valued via a comprehensive electronic cost dictionary, based upon a detailed economic evaluation of renal transplantation in Canada. Medication costs were calculated from hospital pharmacy acquisition costs; basiliximab was assessed a zero cost. RESULTS: The average estimated cost per patient for the first year after transplant was $55,393 (Canadian dollars) for placebo and $50,839 for basiliximab, rising to $141,690 and $130,592, respectively, after 5 years. A principal component of the cost in both groups was accrued during the initial transplant hospitalization ($14,663 for standard therapy and $14,099 for basiliximab). An additional $15,852 and $14,130 was attributable to continued care, graft loss, and dialysis in the two groups, whereas follow-up hospitalization consumed an additional $15,538 for placebo and $13,916 for basiliximab. The mean incremental cost of dialysis was $5,397 for placebo compared with $3,821 for basiliximab, whereas incremental costs of graft loss were $2,548 compared with $2,295 in the two treatment groups. The principal costs associated with repeat admission to the transplant ward and the general ward were marginally higher for placebo ($7,395 vs. $6,300 and $5,986 vs. $4,625). Treatment of acute rejection and maintenance immunosuppressive drug use were associated with only limited savings as a result of basiliximab (savings <$200 each). Sensitivity analysis indicated that the most influential parameters affecting the savings as a result of using basiliximab were a reduction in the duration of initial and repeat hospitalization followed by the reduced risks of acute rejection and graft loss. CONCLUSIONS: Before accounting for the cost of the therapy itself, basiliximab produces an estimated economic saving of $4,554 during the first year after transplant, of which $3,344 is attributable to the reduced costs of graft dysfunction, including graft loss and dialysis ($1,722) and follow-up hospitalizations ($1,622). When marketed, basiliximab is expected to cost approximately $3,000 per course (two doses of 20 mg), resulting in a net first-year saving of $1,554. Under these circumstances, basiliximab can be considered a dominant therapy in renal transplantation.

Antibodies, Monoclonal↗
PubMed2003

Use of basiliximab with mycophenolate mofetil in kidney transplantation.

INTRODUCTION: Randomized, placebo-controlled studies have determined that administration of basiliximab (chimeric IL-2 receptor antagonist) decreases the acute rejection rate in kidney transplantation when used in combination with cyclosporine, azathioprine, and steroids. We report our experience using basiliximab with mycophenolate mofetil, a calcineurin inhibitor, and steroids in kidney transplantation. METHODS: We retrospectively analyzed 127 patients who received their first kidney transplant between September 1, 1998, and December 30, 2000, including 59 who received basiliximab (22 living and 37 cadaveric donor recipients) and the 68 that did not receive this antibody (31 living and 37 cadaveric donor recipients). The groups were demographically comparable for risk factors such as race, peak of panel-reactive antibody, delayed graft function, donor age, and cold ischemia time. The analysis assessed serum creatinine levels, acute rejection, cytomegalovirus infection, and posttransplant lymphoproliferative disease incidence as well as patient and graft survival at 6 months. RESULTS: Serum creatinine levels were 3 +/- 3.1 and 2.6 +/- 2.5 mg/dL (P =.346) at discharge, 1.5 +/- 0.6 and 1.7 +/- 1.1 mg/dL (P =.098) at 1 month, and 1.5 +/- 0.7 and 1.6 +/- 0.7 mg/dL (P =.454) at 6 months posttransplantation for patients treated with versus without basiliximab, respectively. Only one episode of acute rejection was seen among patients treated with basiliximab within 1 month posttransplantation versus three episodes among patients treated without basiliximab (P =.382). Three patients (5.1%) treated with basiliximab and two patients (2.9%) treated without basiliximab developed acute rejection within 6 months posttransplantation (P =.536). Patient and graft survivals at 6 months posttransplantation were not significantly different between patients treated with versus without basiliximab (100% and 100% versus 100% and 98.3%, respectively). There was no increased incidence of cytomegalovirus infection with the use of basiliximab (5.1% vs 5.9%, P =.844). There was only one case of posttransplant lymphoproliferative disease within 6 months posttransplantation in a patient treated without basiliximab. CONCLUSION: These data suggest that the routine addition of basiliximab to a mycophenolate mofetil-based regimens does not appear to be warranted. A larger prospective randomized study with longer follow-up is needed to confirm these results.

Adult↗
PubMed2002

Basiliximab in pediatric liver transplantation: a pharmacokinetic-derived dosing algorithm.

The pharmacokinetics and immunodynamics of basiliximab were assessed in 37 pediatric de novo liver allograft recipients to rationally design a dose regimen for this age-group. In part one of the study, patients were given 12 mg/m2 basiliximab by bolus intravenous injection after organ perfusion and on day 4 after transplant. An interim pharmacokinetic evaluation supported a fixed-dose approach for part two of the study in which infants and children received two 10-mg doses of basiliximab and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for screening for anti-idiotype antibodies and analysis of basiliximab and soluble interleukin-2 receptor (IL-2R) concentrations. Basiliximab clearance in infants and children < 9 yr of age (n = 30) was reduced by approximately 50% compared with adults from a previous study and was independent of age to 9 yr, weight to 30 kg, and body surface area to 1.0 m2. Clearance in children and adolescents 9-14 yr of age (n = 7) approached or reached adult values. An average of 15% of the dose was eliminated via drained ascites fluid, and drug clearance via this route averaged 29% of total body clearance. Patients with > 5 L of ascites fluid drainage tended to have lower systemic exposure to basiliximab. CD25-saturating basiliximab concentrations were maintained for 27 +/- 9 days in part one of the study (mg/m2 dosing) with infants exhibiting the lowest durations. CD25 saturation lasted 37 +/- 11 days in part two of the study, based on the fixed-dose regimen (p = 0.004 vs. mg/mg2 dosing), but did not show the age-related bias observed in part one of the study. Anti-idiotype antibodies were detected in four patients, but this did not influence the clearance of basiliximab or duration of CD25 saturation. All 40 enrolled patients were included in the intent-to-treat clinical analysis. Episodes of acute rejection occurred in 22 patients (55%) during the first 12 months post-transplant. Three patients experienced loss of their graft as a result of technical complications, and six patients died during the 12-month study. Basiliximab was well tolerated by intravenous bolus injection, with no cytokine-release syndrome or other infusion-related adverse events. Hence, basiliximab was safe and well tolerated in pediatric patients undergoing orthotopic liver transplantation. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients < 35 kg in weight should receive two 10-mg doses and those > or = 35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose should be given within 6 h after organ perfusion and the second on day 4 after transplantation. A supplemental dose may be considered for patients with a large volume of drained ascites fluid relative to body size.

Adolescent↗
PubMed2001

Basiliximab induction improves the outcome of renal transplants in children and adolescents.

Thirty-two children and adolescents received their renal transplant at the Montefiore Medical Center, in New York, between October 1996 and May 2000. Twenty-four patients received basiliximab, in addition to tacrolimus and steroids (basiliximab group). The remaining eight patients received only tacrolimus and steroids (non-basiliximab group). The 1-year patient survival rate was 100% in both groups. The 1-year graft survival rate was 87.5% for the basiliximab group and 75% for the non-basiliximab group (P=0.45). The rates of acute rejection in the basiliximab and non-basiliximab groups were 26% and 43%, respectively (P=0.36). However, in recipients with <or=3 HLA mismatches, the rate of acute rejection was zero in the basiliximab group, and 40% in the non-basiliximab group (P=0.04). The beneficial effect occurred despite the fact that tacrolimus was maintained at below the target levels. There were no adverse events directly attributable to the administration of basiliximab. There were no cases of opportunistic infections or post-transplant lymphoproliferative disease. In summary, addition of basiliximab to tacrolimus and prednisone significantly decreased the rate of acute rejection in well-matched patients. Moreover, this effect was manifest at lower, and therefore less toxic, tacrolimus levels.

Adolescent↗
PubMed2005

Sequential blood level monitoring of basiliximab during multisession plasmapheresis in a kidney transplant recipient.

Basiliximab, a chimeric monoclonal antibody against the alpha chain of the interleukin-2 receptor (IL-2R) has been used in renal transplant patients. We monitored sequential blood concentrations of basiliximab in a patient who received a kidney transplant with basiliximab-based immunosuppression together with multiple sessions of plasmapheresis. A 34-year-old man received a living-related kidney transplant with induction immunosuppression including tacrolimus, mycophenolate, methylprednisolone, and basiliximab. Severe antibody-mediated acute rejection lead to a requirement for hemodialysis. Deoxyspergualin was administered for 10 days at a daily dose of 5 mg/kg combined with eight sessions of double filtration plasmapheresis (DFPP). After treatment, the serum creatinine returned to 0.95 mg/dL, and there were no major complications or infections. Sequential basiliximab blood levels of the patient were monitored following transplantation. The serum basiliximab concentration decreased by 72.4% after five consecutive DFPPs, and by 87.6% after eight DFPP sessions. The elimination rate of basiliximab (DeltaBLX) was 6.1% before DFPP, but increased over eight DFPPs to 20.5%. Serum basiliximab concentrations declined to 0.16 microg/mL on day 33, which is below the IL-2R saturation concentration (0.2 microg/mL). Multiple sessions of plasmapheresis using DFPP enhanced the elimination of serum basiliximab at an average elimination rate of 19.1%. In the patient reported on here, the serum basiliximab concentration fell to below the IL-2R saturation level (0.2 microg/mL) within 1 month of living-related kidney transplantation. We recommend that additional basiliximab infusions be considered for cases undergoing more than three plasmapheresis sessions.

Acute Disease↗
PubMed2001

Differential influence of azathioprine and mycophenolate mofetil on the disposition of basiliximab in renal transplant patients.

Pharmacokinetic sampling was performed in two multicenter trials in which basiliximab (anti-CD25 monoclonal antibody) was administered with triple immunosuppression consisting of cyclosporine microemulsion, corticosteroids, and either azathioprine or mycophenolate mofetil. Blood samples were collected over 12 wk post-transplant from 31 azathioprine-treated and 66 mycophenolate mofetil-treated patients. Empirical Bayes estimates of each patient's basiliximab disposition parameters were derived and the duration of CD25 saturation was estimated as the time over which serum concentrations exceeded 0.2 microg/mL as confirmed by flow cytometry measurements. Basiliximab clearance was 29+/-14 mL/h when coadministered with azathioprine and 18+/-8 mL/h with mycophenolate mofetil. Both were significantly lower compared with a clearance of 37+/-15 mL/h from a previous study of basiliximab with dual therapy (p<0.001). As a consequence of the lower clearance of basiliximab, the durations of CD25 saturation were prolonged in the presence of azathioprine (50+/-20 d; range, 13--84) and mycophenolate mofetil (59+/-17 d; range, 28--94) compared with dual therapy (36+/-14 d; range, 12--91). A total of 27 acute rejection episodes occurred during the first 6 months in the two studies. Durations of CD25 saturation were not different in these patients compared with those who remained rejection-free in each study. A single patient among 57 who were screened developed anti-idiotype antibodies to basiliximab. The average duration of CD25 saturation was prolonged by 39 and 64% in the presence of azathioprine and mycophenolate mofetil, respectively. This graded effect was also observed for basiliximab clearance and may be due in part to a differentially reduced humoral response to basiliximab. Nonetheless, the range of CD25 saturation durations and basiliximab clearances did not extend outside the range when basiliximab was used with dual therapy in the absence of these agents. Hence, no dosing adjustment is deemed necessary when basiliximab is used in triple immunosuppressive therapy including either azathioprine or mycophenolate mofetil.

Antibodies, Anti-Idiotypic↗
PubMed1999

Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. United States Simulect Renal Study Group.

BACKGROUND: A double-blind, placebo-controlled phase III study was performed to assess whether basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, reduced the incidence of acute rejection episodes in renal allograft recipients. METHODS: A total of 348 patients were randomized into two demographically matched, equally sized groups treated with either basiliximab or placebo. The dose of basiliximab-20-mg infusions on day 0 and day 4-was selected to block detection of interleukin-2 receptor on 97% of peripheral blood lymphocytes for 30-45 days. All patients received immunosuppressive therapy with cyclosporine microemulsion (Neoral) and steroids. An intent-to-treat analysis of 1-year data assessed the incidence of posttransplant acute rejection episodes, patient and graft survival rates, and the safety and tolerability of basiliximab. RESULTS: Among the eligible 346 patients equally divided into the two treatment groups, basiliximab reduced the proportion of patients who experienced biopsy-confirmed acute rejection episodes by 28%: 61 (35.3%) basiliximab vs. 85 (49.1%) placebo (P=0.009). Graft losses occurred in 9 (5.2%) basiliximab-treated and 12 (6.9%) placebo-treated patients. Five (2.9%) deaths in the basiliximab group and seven (4.0%) in the placebo group occurred. Compared with placebo, a higher fraction of basiliximab patients produced urine in the operating room, and a significantly lower fraction had renal dysfunction in the first month (serum creatinine > or =5 mg(dl) and between 1 and 12 months (serum creatinine > or =3 mg/dl). During the first 12 months, 94 (54%) basiliximab-treated patients experienced serious adverse events, compared with 106 (61%) who received placebo. CONCLUSIONS: Prophylactic basiliximab therapy is well tolerated, has an adverse event profile comparable to placebo, and significantly reduces the number of acute rejection episodes in renal allograft patients within the first year after transplantation.

Acute Disease↗
PubMed1999

Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation. The U.S. Simulect Renal Transplant Study Group.

BACKGROUND: Basiliximab is an interleukin-2 receptor (CD25) chimeric monoclonal antibody used for acute rejection prophylaxis in renal transplants. In the context of a randomized, double-blind efficacy trial, its population pharmacokinetics and potential exposure-response relationships were explored in de novo kidney allograft recipients receiving 40 mg basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppressive therapy with cyclosporine microemulsion and corticosteroids. METHODS: Serial blood samples (8.2+/-1.3 per patient) were collected over 12 weeks after transplant from 169 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. The duration of CD25 saturation was estimated as the time over which serum basiliximab concentrations exceeded 0.2 microg/ml. The relationships between pharmacokinetic parameters and demographic-clinical covariates were explored by regression methods and unpaired t-tests. RESULTS: Basiliximab clearance was 36.7+/-15.2 ml/hr, distribution volume 8.0+/-2.4 L, and half life 7.4+/-3.0 days. Patient weight (range, 44-131 kg) and age (range, 20-69 yrs) each contributed < or =6% to the variability in clearance and volume. Gender, ethnic group, and the presence of proteinuria had no clinically relevant influences on basiliximab disposition. Receptor-saturating basiliximab concentrations were maintained for 36+/-14 days (range, 12-91). There was no apparent relationship between the incidence or day of onset of acute rejection episodes during CD25 saturation and basiliximab concentration (range, 0.2-5.0 microg/ml). In patients who experienced a rejection episode after basiliximab was eliminated from serum (n=33), basiliximab had not been cleared faster than in their rejection-free peers (P=0.322) nor had CD25 been saturated for a shorter period of time (33+/-13 days vs. 37+/-14 days for rejection-free patients, P=0.162). CONCLUSIONS: There were no demographic or clinical subpopulations not adequately treated with the standard basiliximab dosing regimen. Over the range of CD25 suppression durations observed in this study, extended periods of receptor blockade did not seem to confer an immunoprophylactic advantage compared with shorter periods of receptor suppression.

Adult↗
PubMed2001

Basiliximab versus antithymocyte globulin for prevention of acute renal allograft rejection.

BACKGROUND: Basiliximab (Simulect), a high-affinity chimeric, monoclonal antibody directed against the alpha chain of human interleukin-2 receptor (CD25), reduces the incidence of acute renal allograft rejection when used in combination with cyclosporine (Neoral) and steroids. This study was designed to compare the safety and efficacy of basiliximab to polyclonal anti-T-cell (ATGAM) therapy for the prevention of acute rejection in de novo renal transplant recipients. METHODS: This 1-year, open-label, randomized trial was conducted in recipients of cadaveric or living-related donor renal transplants. All patients received cyclosporine (Neoral), mycophenolate mofetil (CellCept, MMF), and corticosteroids. Patients who were randomized to basiliximab therapy received a 20 mg i.v. bolus dose on days 0 and 4, and the majority of patients were initiated on cyclosporine within 48 hr of transplantation. Patients who were randomized to antithymocyte globulin therapy (ATGAM, ATG) received 15 mg/day i.v. within 48 hr of transplant and continued treatment for up to 14 days; ATG was stopped once therapeutic cyclosporine blood levels were achieved. The initiation of cyclosporine use was delayed in the ATG group until renal function was established (serum creatinine <3.0 mg/dl or 50% fall from baseline). RESULTS: Of the 138 randomized patients, 135 received at least 1 dose of study medication (70 patients, basiliximab; 65 patients, ATG). Demographic characteristics were similar between the basiliximab and ATG-treatment groups. At 12 months, the rate of biopsy-proven acute rejection was 19% and 20%, respectively, in the basiliximab and ATG groups. Although the overall profile of adverse events was similar between basiliximab- and ATG-treated patients, adverse events considered by the investigators to be associated with the study drug occurred more often among patients receiving ATG (42% vs. 11% with basiliximab). CONCLUSIONS: Basiliximab combined with early initiation of cyclosporine therapy resulted in low acute rejection rates similar to those achieved with ATG combined with delayed cyclosporine. Basiliximab therapy showed an excellent safety profile, with no increases in malignancies, infections, or deaths. Based on its convenient two-dose, body-weight independent regimen and comparable effectiveness to ATG, basiliximab is an attractive choice for the prevention of acute rejection episodes in renal transplant patients.

Acute Disease↗
PubMed2003

Anaphylactic shock caused by immunoglobulin E sensitization after retreatment with the chimeric anti-interleukin-2 receptor monoclonal antibody basiliximab.

BACKGROUND: Repeated administration of chimeric or humanized monoclonal antibodies is generally well tolerated. Anti-idiotypic sensitization is rare and is considered to be of no clinical significance. We observed a child who experienced anaphylactic shock when he received a second course of basiliximab at the time of his second renal transplantation. We therefore searched for the presence of anti-basiliximab immunoglobulin (Ig) E in this patient. METHODS: Serum levels of anti-basiliximab IgE, assay of the anti-murine reactivity of circulating anti-basiliximab IgE, and assays for serum anti-mouse antibodies and global anti-basiliximab anti-idiotypic antibodies were carried out by enzyme-linked immunosorbent assay. Anti-basiliximab IgE antibodies on circulating basophils were evaluated by the ability of the patient's blood to produce leukotrienes in vitro after exposure to basiliximab. RESULTS: Sequential assays of serum samples by enzyme-linked immunosorbent assay indicated that anti-basiliximab IgE antibodies appeared after the second basiliximab course. There was no IgE reactivity toward a control murine IgG2a monoclonal antibody (mAb), indicating that the IgE response was directed exclusively against basiliximab idiotypes. There was no IgE reactivity against the humanized anti-interleukin-2 receptor mAb daclizumab, which was derived from a distinct parental murine mAb. Patient basophils harvested months after the anaphylactic shock produced leukotrienes in vitro on exposure to basiliximab. CONCLUSIONS: Patients exposed to chimeric antibodies may develop an anti-idiotypic IgE response that can trigger anaphylactic shock on further exposure. Specific anti-idiotypic IgE may be bound to basophils even in the absence of circulating IgE.

Anaphylaxis↗
PubMed2005

Multicenter, randomized study of the effectiveness of basiliximab in avoiding addition of steroids to cyclosporine a monotherapy in renal transplant recipients.

BACKGROUND: Steroid therapy is associated with an increased risk of cardiovascular events and well-documented adverse effects, but two thirds of patients initiated on monotherapy with cyclosporine A (CsA) microemulsion require addition of steroids. METHODS: In this 12-month randomized, double-blind, multicenter study, 108 renal transplant recipients were randomized and received basiliximab (n=52) or placebo (n=56) to assess whether basiliximab reduces the need for addition of steroids or other adjunctive immunosuppressive drugs to CsA monotherapy. RESULTS: The primary endpoint of the study (requirement for additional immunosuppression at 12 months posttransplant) occurred significantly less frequently with basiliximab (54%) than placebo (73%) (P=0.046). By the end of the study, 25% of basiliximab-treated patients were receiving maintenance steroids versus 61% of placebo-treated patients (P=0.0006). During the trial, 33% of basiliximab-treated patients received oral steroids at some time compared with 61% of placebo-treated patients (P=0.004). The proportion of patients experiencing biopsy-proven rejection was not significantly different between the basiliximab (29%) and placebo (43%) groups (P=0.16). Median serum creatinine at 12 months was 141 mumol/L with basiliximab and 164 mumol/L with placebo (not significant). One-year graft and patient survivals were 88% and 98% for basiliximab and 88% and 96% for placebo (not significant), respectively. Adverse events were similar in the basiliximab and placebo treatment groups. CONCLUSIONS: These findings demonstrate that the addition of basiliximab significantly reduces the need to modify the initial treatment regimen in patients scheduled to receive steroid-free CsA therapy, suggesting that basiliximab induction may be useful as a strategy in other steroid-avoidance regimens.

Acute Disease↗
PubMed2005

Basiliximab (Simulect) in renal transplantation with high risk for delayed graft function.

BACKGROUND: Basiliximab (Simulect) is effective in reducing episodes of acute rejection in renal transplantation. Delayed graft function (DGF) predisposes to acute rejection and shortens graft survival. The aim of this study was to determine the effects of basiliximab in renal transplantation recipients at high risk for DGF. METHODS: We studied 87 patients (mean age, 59 years), 42 of whom received basiliximab, 20 mg before transplantation and 20 mg on day 4. This cohort was compared with 45 patients without basiliximab. All received cyclosporine (51%) or tacrolimus (49%), mycophenolate mofetil, and steroids. DGF was defined as the requirement for dialysis within the first week after transplantation or failure to improve preexisting renal function. High-risk factors for DGF were cold ischemia time, recipient and donor age, non-heart-beating donor, HLA matching, and panel reactive antibody (PRA). RESULTS: The incidence of DGF was 18 (43%) in the basiliximab group versus 28 (62%) in the other patients (P = .07). When allografts from non-heart-beating donors were excluded, this incidence was 14 (38%) in the basiliximab group versus 28 (62%) in the other patients (P = .04). Regression analysis showed basiliximab to be a protective factor: 0.26 (range, 0.09-0.76). Basiliximab was well tolerated, and complications were similar in both groups. CONCLUSIONS: Basiliximab reduced the incidence of DGF in patients who received a high-risk allograft. It was well tolerated, and no adverse events were reported. The use of basiliximab may be considered in patients receiving an allograft who are at high risk for DGF.

Antibodies, Monoclonal↗
PubMed1997

Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group.

BACKGROUND: Currently available immunosuppressive regimens for cadaver-kidney recipients are far from ideal because acute-rejection episodes occur in about 30% to 50% of these patients. In the phase III study described here we assessed the ability of basiliximab, a chimeric interleukin (IL)-2 receptor monoclonal antibody, to prevent acute-rejection episodes in renal allograft recipients. METHODS: 380 adult recipients of a primary cadaveric kidney transplant were randomly allocated, in this double-blind trial, to receive a 20 mg infusion of basiliximab on day 0 (day of surgery) and on day 4, to provide IL-2-receptor suppression for 4-6 weeks (n=193), or to receive placebo (n=187). Both groups received baseline dual immunosuppressive therapy with cyclosporin and steroids throughout the study. The primary outcome measure was incidence of acute-rejection episodes during the 6 months after transplantation. Safety and tolerability were monitored over the 12 months of the study. FINDINGS: 376 patients were eligible for intention-to-treat analysis (basiliximab, n=190; placebo, n=186). No significant differences in patient characteristics were apparent. The incidence of biopsy-confirmed acute rejection 6 months after transplantation was 51 (29.8%) of 171 in the basiliximab group compared with 73 (44.0%) of 166 in the placebo group (32% reduction; 14.2% difference [95% Kaplan-Meier CIs 3% to 24%], p=0.012). The incidence of steroid-resistant first rejection episodes that required antibody therapy was significantly lower in the basiliximab group (10% vs 23.1%, 13.1% difference [5.4% to 20.8%], p<0.001). At weeks 2 and 4 post-transplantation, the mean daily dose of steroids was significantly higher in the placebo group (p<0.001 with one-way analysis of variance). The incidence of graft loss at 12 months post-transplantation was 23 (12.1%) of 190 in the basiliximab group and 25 (13.4%) of 186 in the placebo group (1.3% difference [-5% to 9%], p=0.591). The incidence of infection and other adverse events was similar in the two treatment groups. The acute tolerability of basiliximab was excellent, with no evidence of cytokine-release syndrome. 14 deaths (basiliximab n=9; placebo n=5; -2.0% difference [-6% to 2%], p=0.293) occurred during the 12-month study and a further three deaths (basiliximab n=1; placebo n=2) occurred within the 380-day cut-off period. One post-transplantation lymphoproliferative disorder was recorded in each group. INTERPRETATION: Prophylaxis with 40 mg basiliximab reduces the incidence of acute rejection episodes significantly, with no clinically relevant safety or tolerability concerns.

Acute Disease↗
PubMedDate not supplied

Blockade of intragraft IL-2 receptor-alpha by basiliximab is insufficient to prevent activation of liver graft infiltrating cells.

Treatment with basiliximab, a CD25 (Interleukin-2 receptor-alpha; IL-2Ralpha)-blocking human-murine chimeric antibody, reduces the incidence of acute rejections after organ transplantation, but rejection is not completely prevented. We investigated whether rejections during basiliximab treatment were due to insufficient exposure to the antibody or to incomplete blockade of intragraft CD25, and whether CD25-blockade affected activation of liver transplant infiltrating cells. Twenty-seven basiliximab-treated liver transplant recipients and seven patients not treated with basiliximab, from which post-transplant liver biopsies were available, were retrospectively selected for this study. Rejectors among the basiliximab-treated patients (n=11) had not cleared basiliximab from their blood at a faster rate than non-rejectors (n=16). Rejections within the period of saturating serum basiliximab concentrations were in most cases not due to insufficient intragraft CD25-blockade: in eight out of eleven rejection biopsies obtained during this period CD25 on graft-infiltrating cells was completely coated by basiliximab. Despite CD25 blockade, portal infiltrates in these biopsies showed similar expression of the proliferation-associated antigen Ki-67 and of the cytotoxic effector molecules granzyme A and B as those in rejection biopsies obtained from patients not treated with basiliximab. In conclusion, basiliximab treatment of liver transplant patients results in blockade of intragraft CD25, but nevertheless cells in rejection infiltrates are strongly activated, probably by a mechanism bypassing the IL-2Ralpha.

Antibodies, Monoclonal↗
PubMed1999

Screening for basiliximab exposure-response relationships in renal allotransplantation.

The immunosuppressant basiliximab--a chimeric monoclonal antibody specific to the interleukin-2 receptor on activated T-lymphocytes--significantly reduces the incidence of acute cellular rejection following renal transplantation. Screening for exposure-response relationships was performed within a randomized, blinded, placebo-controlled efficacy trial in which patients received 40 mg basiliximab (20 mg on days 0 and 4) by intravenous infusion in addition to cyclosporine and corticosteroids. In a subset of patients, serum samples were collected pre-transplant and once in weeks 2, 3 and 4 for determination of basiliximab concentrations. A population pharmacostatistical model was used to derive individual empirical Bayes estimates of each patient's pharmacokinetic parameters. Biopsy-confirmed acute rejection episodes were recorded to month 6 post-transplant. Forty basiliximab-treated patients were evaluated, 30 men and 10 women, aged 48 +/- 12 yr (range, 24-73) and weighing 72.4 +/- 12.9 kg (range, 52.5-107.5). The basiliximab distribution volume was 7.5 +/- 1.7 L, the half-life 7.5 +/- 2.5 d and the clearance 33 +/- 12 mL/h. There was no clinically relevant influence of weight, age, or gender on basiliximab disposition. Receptor-saturating serum basiliximab concentrations (> 0.2 microgram/mL) were maintained for 41 +/- 23 d. Twenty-five patients remained rejection-free over the 6-month observation period, while a total of 26 biopsy-confirmed acute rejection episodes occurred in the remaining 14 patients. Of these episodes, 12 occurred during receptor blockade. No apparent relationship to basiliximab concentration on the day of onset was observed range, 0.1-9.0 microgram/mL) nor did the time of suppression offset represent a period of increased risk for rejection episodes. Fourteen rejection episodes occurred after basiliximab had cleared from the serum. The durations of receptor suppression preceding these events did not differ compared with those in patients who remained rejection-free: 32 +/- 11 versus 45 +/- 26 d, respectively (p = 0.1269). Given the durations of receptor saturation achieved with the chosen basiliximab regimen, this screen for exposure-response relationships did not identify the duration of receptor saturation in peripheral blood as a predictive factor for acute rejection episodes. Further exploration for exposure-effect relationships in a larger population is warranted.

Adult↗