General

Rituximab binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes.^1,2 The antigen is also expressed on > 90% of B-cell non-Hodgkin's lymphomas (NHL),³ but is not found on hematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissues.⁴ CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation,⁴ and possibly functions as a calcium ion channel.⁵ CD20 is not shed from the cell surface and does not internalize upon antibody binding.⁶ Free CD20 antigen is not found in the circulation.²

B-cells are believed to play a role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, B-cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T cell activation, and/or pro-inflammatory cytokine production.⁷

Preclinical Pharmacology and Toxicology

Mechanism of Action

The Fab domain of Rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC)⁸ and antibody-dependent cell mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line.⁹

Normal Tissue Cross-reactivity

Rituximab binding was observed on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. Little or no binding was observed in the non-lymphoid tissues examined.

Pharmacokinetics

In patients with NHL given single doses at 10, 50, 100, 250 or 500 mg/m² as an IV infusion, serum levels and the half-life of Rituximab were proportional to dose.¹⁰ In 14 patients given 375 mg/m² as an IV infusion for 4 weekly doses, the mean serum half-life was 76.3 hours (range, 31.5 to 152.6 hours) after the first infusion and 205.8 hours (range, 83.9 to 407.0 hours); after the fourth infusion.^{11, 12, 13} The wide range of half-lives may reflect the variable tumor burden among patients and the changes in CD20-positive (normal and malignant) B-cell populations upon repeated administrations.

Rituxan at a dose of 375 mg/m² was administered as an IV infusion at weekly intervals for 4 doses to 203 patients with NHL naive to Rituxan.^{13, 14} The mean Cmax following the fourth infusion was 486 µ g/mL (range, 77.5-996.6 µ g/mL). The peak and trough serum levels of Rituximab were inversely correlated with baseline values for the number of circulating CD20-positive B-cells and measures of disease burden. Median steady-state serum levels were higher for responders compared with nonresponders; however, no difference was found in the rate of elimination as measured by serum half-life. Serum levels were higher in patients with International Working Formulation (IWF) subtypes B, C, and D as compared with those with subtype A.^11,14 Rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment.

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