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Pharmacology: Simulect is a murine/human chimeric monoclonal antibody (IgG1k) 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 specifically 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. As concentrations fall below this level, expression of the CD25 antigen returns to pre-therapy values within 1-2 weeks. Simulect does not cause cytokine release or myelosuppression.
Clinical Studies: The efficacy of Simulect in prophylaxis of organ rejection in de novo renal transplantation has been demonstrated in placebo-controlled studies. Results from 2 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.
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 a clinical trial, 6 (3.5%) developed a HAMA response.
Pharmacokinetics: Single- 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 IV infusion of 20 mg over 30 min 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/hr.
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 (20-69 years), gender or race.
No data exist on the use of Simulect in neonates or infants <2 years. In 1 clinical study in 8 paediatric de novo renal transplant patients 2-12 years, the central distribution volume was 1.7±0.6 L, half-life was 9.4±4.9 days, and clearance was 20±4 mL/hr. Clearance and volume were not influenced by age (2-12 years), body weight (9-37 kg) or body surface area (0.44-1.2 m2).
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/hr. Contributing to clearance were drug loss via drained ascites fluid and postoperative bleeding. Offsetting the faster drug clearance was a lower receptor-saturating concentration threshold of 0.1 mcg/mL in this population. Hence, the duration of IL-2Rα blockade at a given Simulect dose level is similar to that seen in adult renal transplant patients.
Toxicology: Preclinical Safety Data: No local irritation potential was observed in a sensitive rabbit model IV injected with up to 4 mg/mL of basiliximab.
No toxicity was observed when rhesus monkeys received IV doses of up to 5 mg/kg basiliximab twice weekly for 4 weeks. The highest dose resulted in approximately 20 times the systemic exposure (Cmax) observed in renal transplant patients given the recommended clinical dose together with concomitant immunosuppressive therapy.
No maternal toxicity, embryotoxicity or teratogenicity was observed in cynomolgus monkeys 100 days postcoitum following bolus injections of up to 5 mg/kg basiliximab administered twice weekly during the organogenesis period.
No mutagenic potential was observed in vitro.
