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Pharmacotherapeutic Group: Interleukin inhibitors.
Pharmacology: Pharmacodynamics: Simulect is a murine/human chimeric monoclonal antibody (IgG1κ) that is directed against the interleukin-2 receptor alpha-chain (CD25 antigen), which is expressed on the surface of T-lymphocytes in response to antigenic challenge. Simulect specifically binds with high affinity (KD-value 0.1 nM) to the CD25 antigen on activated T-lymphocytes expressing the high affinity interleukin-2 receptor and thereby prevents binding of interleukin-2, the signal for T-cell proliferation. Complete and consistent blocking of the interleukin-2 receptor is maintained as long as serum basiliximab levels exceed 0.2 micrograms/mL. As concentrations fall below this level, expression of the CD25 antigen returns to pretherapy values within 1 to 2 weeks. Simulect does not cause myelosuppression.
Pharmacokinetics: Single-dose and multiple-dose pharmacokinetic studies have been conducted in patients undergoing kidney transplantation. Cumulative doses ranged from 15 mg up to 150 mg.
Absorption: Peak serum concentration following intravenous infusion of 20 mg over 30 minutes is 7.1 ± 5.1 mg/L. There is a proportional increase in Cmax and AUC with dose up to the highest tested single dose of 60 mg.
Distribution: The volume of distribution at steady state is 8.6 ± 4.1 L. The extent and degree of distribution to various body compartments have not been fully studied. In vitro studies using human tissues indicate that Simulect binds only to lymphocytes and macrophages/monocytes.
Metabolism: Not applicable.
Elimination: The terminal half-life is 7.2 ± 3.2 days. Total body clearance is 41 ± 19 mL/h.
Characteristics in patients: No clinically relevant influence of body weight or gender on distribution volume or clearance has been observed in adult patients. Elimination half-life was not influenced by age (20 to 69 years), gender or race.
Disposition in adult liver transplant patients is characterized by a steady-state distribution volume of 7.5 ± 2.5 L, half-life of 4.1 ± 2.1 days and clearance of 75 ± 24 mL/h. Contributing to clearance were drug loss via drained ascites fluid and post-operative bleeding. Offsetting the faster drug clearance was a lower receptor-saturating concentration threshold of 0.1 micrograms/mL in this population. Hence, the duration of IL-2R alpha blockade at a given Simulect dose level is similar to that seen in adult renal transplant patients.
Pediatrics: The pharmacokinetics of Simulect were assessed in 39 pediatric de novo renal transplantation patients. In infants and children (age 1 to 11 years, n=25), the steady-state distribution volume was 4.8 ± 2.1 L, half-life was 9.5 ± 4.5 days and clearance was 17 ± 6 mL/h. Distribution volume and clearance are reduced by about 50% compared to adult renal transplantation patients. Disposition parameters were not influenced to a clinically relevant extent by age (1 to 11 years), body weight (9 to 37 kg) or body surface area (0.44 to 1.20 m2) in this age group. In adolescents (age 12 to 16 years, n=14), the steady-state distribution volume was 7.8 ± 5.1 L, half-life was 9.1 ± 3.9 days and clearance was 31 ± 19 mL/h. Disposition in adolescents was similar to that in adult renal transplantation patients. The relationship between serum concentration and receptor saturation was assessed in 13 patients and was similar to that characterized in adult renal transplantation patients.
Clinical Studies: The efficacy of Simulect in prophylaxis of organ rejection in de novo renal transplantation has been demonstrated in double-blind placebo-controlled studies. Results from two pivotal 12-month multicentre studies comparing Simulect with placebo show that Simulect, used concomitantly with ciclosporin for microemulsion and corticosteroids, significantly reduces the incidence of acute rejection episodes both within 6 (31% vs. 45%, p <0.001) and 12 (33% vs. 48%, p <0.001) months after transplantation. There was no significant difference between Simulect and placebo treated patients in graft survival after 6 and 12 months (at 12 months 32 graft losses on Simulect (9%) and 37 graft losses on placebo (10%)). The incidence of acute rejection episode was substantially lower in patients receiving Simulect and a triple drug immunosuppressive regimen.
Results from two multicentre double-blind studies comparing Simulect with placebo show that Simulect significantly reduces the incidence of acute rejection episodes within 6 months after transplantation when used concomitantly with ciclosporin for microemulsion, corticosteroids, and either azathioprine (21% vs. 35%, p=0.005 Fisher's exact) or mycophenolate mofetil (15% vs. 27%, p=0.046 K-M). Graft loss occurred in 6% of Simulect and 10% of placebo patients by 6 months. The adverse event profile remained comparable between treatment groups.
One 12-month active-controlled randomized open-label study compared Simulect used concomitantly with early ciclosporin for microemulsion to a polyclonal anti-T-lymphocyte immunoglobulin preparation (ATG/ALG) with delayed ciclosporin for microemulsion. Both groups received corticosteroids and mycophenolate mofetil. Biopsy proven rejection occurred in 19% of Simulect and 20% of ATG/ALG treated patients within 12 months post-transplant.
In a pooled analysis of two five-year open-label extension studies (586 patients total), the combined graft and patient survival rates were not statistically different for the Simulect and placebo groups. Extension studies also showed that patients who experienced an acute rejection episode during the first year after transplantation experienced more graft losses and deaths over the five-year follow-up period than patients who had no rejection. These events were not influenced by Simulect.
Simulect was used concomitantly with ciclosporin for microemulsion and steroids in an uncontrolled study in pediatric de novo renal transplant recipients. Acute rejection occurred in 14.6% of patients by 6 months post-transplantation, and in 24.3% by 12 months. Overall the adverse event profile was consistent with general clinical experience in the paediatric renal transplantation population and with the profile in the controlled adult transplantation studies.
Of 339 renal transplant patients treated with Simulect and tested for anti-idiotype antibodies, 4 (1.2%) developed an anti-idiotype antibody response. In a clinical trial with 172 patients receiving Simulect, the incidence of human anti-murine antibody (HAMA) in renal transplantation patients treated with Simulect was 2/138 in patients not exposed to muromonab-CD3 and 4/34 in patients who received muromonab-CD3 concomitantly. The available clinical data on the use of muromonab-CD3 in patients previously treated with Simulect suggest that subsequent use of muromonab-CD3 or other murine anti-lymphocytic antibody preparations is not precluded.
Toxicology: Non-clinical Safety Data: No local irritation potential was observed in a sensitive rabbit model intravenously injected with up to 4 mg/mL of basiliximab.
No toxicity was observed when rhesus monkeys received intravenous doses of either up to 5 mg/kg basiliximab twice weekly for 4 weeks followed by an 8-week withdrawal period or 24 mg/kg basiliximab weekly for 39 weeks followed by a 13-week withdrawal period. The highest dose resulted in approximately 1000 times the systemic exposure (AUC) observed in renal transplant patients given the recommended clinical dose together with concomitant immunosuppressive therapy.
No maternal toxicity, embryotoxicity, or teratogenicity was observed in cynomolgous monkeys 100 days post coitum following intravenous bolus injections of up to 5 mg/kg basiliximab administered twice weekly during the organogenesis period.
Formal non-clinical studies on the potential effects of basiliximab on fertility have not been conducted (see USE IN PREGNANCY & LACTATION).
No mutagenic potential was observed in vitro.
