Amy Morgan Wood

Am J Health Syst Pharm. 2001;58(3) 

In This Article

Pharmacology and Pharmacokinetics of Rituximab

Antibodies are Y-shaped structures consisting of two identical heavy chains and two identical light chains connected by disulfide bonds (Figure 2). The proteolytic cleavage of antibodies by papain produces two antigen-binding fragments (Fab fragments) and a crystallizable fragment (Fc fragment). The upper arms of the Y, containing both variable-sequence and constant-sequence regions, form the Fab pieces. The Fc piece, which is recognized by specific receptors on human effector cells, consists of the portions of the heavy chains that make up the stem of the Y.

Figure 2.

Diagram of structure of rituximab. Rituximab is a chimeric antibody of the immunoglobulin G1 kappa type with murine anti-CD20 variable-sequence regions (filled areas) and human constant-sequence regions (open areas).

The chimeric structure of rituximab comprises human IgG 1 and kappa-chain constant regions and heavy- and light-chain variable regions from a murine antibody to CD20 (Figure 2).[40] The murine variable regions selectively bind to the CD20 antigen expressed on the surface of both normal B lymphocytes and most B-cell lymphomas. The presence of a human constant region allows rituximab to bind to Fc receptors on human effector cells (e.g., lymphoma cells, macrophages, and neutrophils) to mediate both complement- dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity and decreases its immunogenicity. [40,49] In vitro, rituximab has been shown to inhibit cell proliferation, induce apoptosis, and sensitize lymphoma cells to the effects of certain chemotherapy agents.[69,70] This synergistic interaction suggests the potential for enhanced treatment efficacy when rituximab and chemotherapy are combined and encourages further investigation in patients with relapsing disease. After rituximab administration, antibody-coated B cells are rapidly depleted from peripheral blood, lymph nodes, and bone marrow.[40]

Pharmacokinetic analysis of data from 166 patients treated with rituximab 375 mg/m 2 once weekly for four doses over 22 days revealed a steady rise in preinfusion and postinfusion serum antibody levels with each rituximab dose.[71] Moreover, detectable antibody levels were still present one, three, and six months after the end of treatment. Consistent with these findings, the elimination half-life of rituximab increased from a mean ± S.D. of 76.3 ± 31.1 hours after the first infusion to 205.8 ± 95.0 hours after the fourth and final infusion. Clearance was 38.2 mL/hr after the first dose and 9.2 mL/hr after the fourth. Prolongation of rituximab's half-life is probably due to the absence of circulating CD20-positive B cells, which bind antibodies during initial infusions. It is also likely that prior rituximab saturation of involved lymphnode sites would increase antibody availability and decrease clearance.

Several important serum concentration- response relationships have been observed.[49,51,55,71] First, antibody levels were significantly higher in patients who responded to treatment than in nonresponders, becoming significant by the second preinfusion and fourth postinfusion determinations and persisting throughout the assessed posttreatment period. In addition, serum antibody levels were inversely correlated with baseline lymphocyte counts, as well as with two measures of baseline tumor bulk. It is believed that serum antibody accumulation and long-term persistence are major contributors to the achievement and maintenance of a therapeutic response to rituximab therapy. Finally, serum rituximab levels were lower in patients with IWF type A NHL, which may be related to a higher tumor burden or reduced CD20 expression. These findings suggest a potential benefit of using rituximab in higher dosages or over prolonged periods in patients with bulky disease and those not responding to initial treatment.


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