Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Interleukin inhibitors; ATC code: L04AC02.
Mechanism of action
Basiliximab is a murine/human chimeric monoclonal antibody (IgG1κ) 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. Basiliximab 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 (IL-2R) and thereby prevents binding of interleukin-2, a critical signal for T-cell proliferation in the cellular immune response involved in allograft rejection.
Complete and consistent blocking of the interleukin-2 receptor is maintained as long as serum basiliximab levels exceed 0.2 μg/ml/ (usually up to 4–6 weeks after administration). As concentrations fall below this level, expression of the CD25 antigen returns to pretherapy values within 1-2 weeks. Basiliximab does not cause myelosuppression.

Clinical efficacy and safety

The efficacy of basiliximab 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 (722 patients in total) comparing basiliximab with placebo show that basiliximab, 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 basiliximab and placebo-treated patients in graft survival after 6 and 12 months (at 12 months 32 graft losses on basiliximab (9%) and 37 graft losses on placebo (10%)). The incidence of acute rejection episode was substantially lower in patients receiving basiliximab and a triple drug immunosuppressive regimen.

Results from two multicentre double-blind studies comparing basiliximab with placebo (463 patients in total) show that basiliximab 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%) or mycophenolate mofetil (15% vs. 27%). Graft loss occurred in 6% of basiliximab-treated and 10% of placebo-treated patients by 6 months. The adverse event profile remained comparable between treatment groups.

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 basiliximab 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 basiliximab.

Paediatric population
The efficacy and safety of basiliximab were evaluated in two paediatric studies.

Basiliximab was used concomitantly with ciclosporin for microemulsion and steroids in an uncontrolled study in 41 paediatric 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.

A 12-month, randomised, placebo-controlled, double-blind, multicentre study investigated basiliximab in combination with ciclosporin for microemulsion, mycophenolate mofetil and steroids in paediatric renal allograft recipients. The primary objective of the study was to demonstrate superiority of this combination versus treatment with ciclosporin for microemulsion, mycophenolate mofetil and steroids in the prevention of acute rejections. Of the 202 patients, 104 were randomised to basiliximab and 98 to placebo. The primary efficacy endpoint, time to first biopsy-proven acute rejection (BPAR) episode or treatment failure defined as graft loss, death or presumptive rejection within the first 6 months post transplantation, occurred in 16.7% of basiliximab-treated patients and 21.7% of placebo- treated patients. When borderline rejections were included in the primary efficacy endpoint, the rates were 26.0% and 23.9% respectively, with no statistically significant difference between the basiliximab- and placebo-treated groups (HR: 1.04, 90% CI: [0.64; 1.68]). The rates of BPAR were 9.4% in the basiliximab group and 17.4% in the placebo group (HR: 0.50, 90% CI: [0.25; 0.99]). When borderline rejections were included, the rates were 20.8% and 19.6% respectively (HR: 1.01, 90% CI: [0.59; 1.72]). The overall safety profiles were similar in both groups. The incidence rates of adverse events and the pattern of adverse events were comparable between the two treatment groups and to be expected for the treatment regimens and the underlying diseases.
Immunogenicity
Of 339 renal transplant patients treated with basiliximab and tested for anti-idiotype antibodies, 4 (1.2%) developed an anti-idiotype antibody response. In a clinical trial with 172 patients receiving basiliximab, the incidence of human antimurine antibody (HAMA) in renal transplantation patients treated with basiliximab 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 basiliximab suggest that subsequent use of muromonab-CD3 or other murine anti-lymphocytic antibody preparations is not precluded.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Adults
Single-dose and multiple-dose pharmacokinetic studies have been conducted in adult patients undergoing kidney transplantation. Cumulative doses ranged from 20 mg up to 60 mg. 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 from 20 mg to 60 mg, the range of single- dose administrations tested.The volume of distribution at steady state was 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 basiliximab binds only to activated lymphocytes and macrophages/monocytes. The terminal half-life was 7.2±3.2 days. Total body clearance was 41±19 ml/h.
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, gender, or race.

Paediatric population
The pharmacokinetics of basiliximab were assessed in 39 paediatric de novo renal transplantation patients. In infants and children (age 1–11 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 (1–11 years), body weight (9–37 kg) or body surface area (0.44–1.20 m2) in this age group. In adolescents (age 12–16 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 characterised in adult renal transplantation patients.