Simulect Mechanism of Action

Pharmacotherapeutic Group: Specific Immunosuppressant. ATC Code: L04AA02.
Pharmacology: Pharmacodynamics: Simulect is a murine/human chimeric monoclonal antibody (Ig_G1κ) that is directed against the interleukin-2 receptor α-chain (CD₂₅ antigen), which is expressed on the surface of T-lymphocytes in response to antigenic challenge. Simulect specially binds 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 mcg/mL (which was 4-6 weeks). As concentration fall below this level, expression of the CD₂₅ antigen returns to pre-therapy values within 1-2 weeks. Simulect does not cause cytine release or myelosuppression.
Soluble IL-2R serum concentrations increase over the first 2-3 weeks following the administration of Simulect, reaching a plateau at levels of 80-120 ng/mL. These levels are maintained while IL-2R sites are saturated by basiliximab. When IL-2R sites are no longer saturated, soluble IL-2R levels fall to pre-transplant levels over the following 1-2 weeks.
Clinical Studies: The efficacy of Simulect in prophylaxis of organ rejection in the Nov renal transplantation has been demonstrated in placebo-controlled studies. Result from 2 pivotal, 12-month multicenter studies comparing Simulect with placebo show that Simulect, used concomitantly with cyclosporin for microemulsion and corticosteroids, significantly reduces the incidence of acute rejection episodes both within 6 and 12 months (at 12 months, 32 graft losses on Simulect (9%) and 37 graft losses on placebo (10%).
Of 268 patients treated with Simulect and tested for anti-idiotype antibodies, only 1 developed an anti-idiotype antibody response. Of 172 patients receiving Simulect in clinical trial, 6 (3.5%) developed a HAMA response.
Pharmacokinetics: Single- and multiple-dose pharmacokinetic studies have been conducted in patient as undergoing kidney transplantation. Cumulative doses ranged from 20-60 mg. Peak serum concentration following IV infusion of 20 mg over 30 min is 7.1±5.1 mg/L. There is a proportional increase in C_max and from 20-60 mg, the range of single-dose administrations tested. 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. The terminal half-life is 7.2±3.2 days. Total body clearance is 41±19 mL/hr.
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 (20-69 years), gender or race.
No data exist on the use of Simulect in neonates or infants <2 years. In 1 clinical study in 12 pediatric de novo renal transplant patients. In children (2-11 years, n=8), the steady-state distribution volume was 5.2±28.1 L, half-life was 11.5±6.3 days and clearance was 17±6 mL/hr. 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 (2-11 years), body weight (9-37 kg) or body surface area (0.44-1.20 m²) in this age group. In adolescents (12-15 years, n=4), the steady-state distribution volume was 10.1±7.6 L, half-life was 7.2±3.6 days and clearance was 45±25 mL/hr. Disposition in adolescents was similar to the adult renal transplantation patients. The relationship between serum concentration and receptor saturation was assessed in 2 patients (2 and 12 years) and was similar to that characterized in adult renal transplantation patients.
Toxicology: Preclinical Safety Data: No toxicity was observed when rhesus monkeys received IV doses of up to 5 mg/kg basiliximab twice weekly for 4 weeks, resulting in approximately 20 times the systemic exposure (C_max) 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 postcoitum following IV bolus injections of up to 5 mg/kg basiliximab administered twice weekly during the organogenesis period.
No mutagenic potential was observed in vitro.