Rituxan (Rituximab) - Description and Clinical Pharmacology

DESCRIPTION

The RITUXAN® (Rituximab) antibody is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG₁ kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences. Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA analysis) and has an approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM.

The chimeric anti-CD20 antibody is produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. The anti-CD20 antibody is purified by affinity and ion exchange chromatography. The purification process includes specific viral inactivation and removal procedures. Rituximab drug product is manufactured from either bulk drug substance manufactured by Genentech, Inc. (US License No. 1048) or utilizing formulated bulk Rituximab supplied by IDEC Pharmaceuticals Corporation (US License No. 1235) under a shared manufacturing arrangement.

RITUXAN is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) administration. RITUXAN is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The product is formulated for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for Injection. The pH is adjusted to 6.5.

CLINICAL PHARMACOLOGY

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

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) ⁷ and antibody-dependent cell mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line.⁸

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.

HUMAN PHARMACOKINETICS/PHARMACODYNAMICS

In patients 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.⁹ 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.^10,11,12 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 naive to RITUXAN. The mean C_max following the fourth infusion was 486 µg/mL (range, 77.5 to 996.6 µg/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. Rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment.

RITUXAN at a dose of 375 mg/m² was administered as an IV infusion at weekly intervals for 8 doses to 37 patients. The mean C_max after 8 infusions was 550 µg/mL (range, 171 to 1177 µg/mL). The mean C_max increased with each successive infusion through the eighth infusion (Table 1).

The pharmacokinetic profile of RITUXAN when administered as 6 infusions of 375 mg/m² in combination with 6 cycles of CHOP chemotherapy was similar to that seen with RITUXAN alone.

Administration of RITUXAN resulted in a rapid and sustained depletion of circulating and tissue-based B cells. Lymph node biopsies performed 14 days after therapy showed a decrease in the percentage of B cells in seven of eight patients who had received single doses of Rituximab >/=100 mg/m².⁹ Among the 166 patients in the pivotal study, circulating B cells (measured as CD19-positive cells) were depleted within the first three doses with sustained depletion for up to 6 to 9 months post-treatment in 83% of patients. Of the responding patients assessed (n = 80), 1% failed to show significant depletion of CD19- positive cells after the third infusion of Rituximab as compared to 19% of the nonresponding patients. B-cell recovery began at approximately 6 months following completion of treatment. Median B-cell levels returned to normal by 12 months following completion of treatment.

There were sustained and statistically significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following Rituximab administration. However, only 14% of patients had reductions in IgM and/or IgG serum levels, resulting in values below the normal range.

CLINICAL STUDIES

Studies with a collective enrollment of 296 patients having relapsed or refractory low-grade or follicular B-cell NHL are described below (Table 2). RITUXAN regimens tested include treatment weekly for 4 doses and treatment weekly for 8 doses. Clinical settings studied were initial treatment, initial treatment of bulky disease, and retreatment.

INITIAL TREATMENT, WEEKLY FOR 4 DOSES

A multicenter, open-label, single-arm study was conducted in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL who received 375 mg/m² of RITUXAN given as an IV infusion weekly for 4 doses. ¹³ Patients with tumor masses >10 cm or with >5,000 lymphocytes/µL in the peripheral blood were excluded from the study. The overall response rate (ORR) was 48% with 6% complete response (CR) and 42% partial response (PR) rates. The median time to onset of response was 50 days and the median duration of response was 11.2 months (range, 1.9 to 42.1+). Disease-related signs and symptoms (including B-symptoms) were present in 23% (39/166) of patients at study entry and resolved in 64% (25/39) of those patients.

In a multivariate analysis, the ORR was higher in patients with IWF B, C, and D histologic subtypes as compared to IWF subtype A (58% vs. 12%), higher in patients whose largest lesion was <5 cm vs. >7 cm (maximum, 21 cm) in greatest diameter (53% vs. 38%), and higher in patients with chemosensitive relapse as compared with chemoresistant (defined as duration of response <3 months) relapse (53% vs. 36%). ORR in patients previously treated with autologous bone marrow transplant was 78% (18/23). The following adverse prognostic factors were not associated with a lower response rate: age >/=60 years, extranodal disease, prior anthracycline therapy, and bone marrow involvement.

INITIAL TREATMENT, WEEKLY FOR 8 DOSES

In a multicenter, single-arm study, 37 patients with relapsed or refractory, low-grade NHL received 375 mg/m² of RITUXAN weekly for 8 doses. The ORR was 57% (CR 14%, PR 43%) with a projected median duration of response of 13.4 months (range, 2.5 to 36.5+). ¹⁴(For information on the higher incidence of Grade 3 and 4 adverse events, see ADVERSE REACTIONS, Risk Factors Associated with Increased Rates of Adverse Events.)

INITIAL TREATMENT, BULKY DISEASE, WEEKLY FOR 4 DOSES

In pooled data from multiple studies of RITUXAN, 39 patients with relapsed or refractory, bulky disease (single lesion >10 cm in diameter), low-grade NHL received 375 mg/m² of RITUXAN weekly for 4 doses. The ORR was 36% (CR 3%, PR 33%) with a median duration of response of 6.9 months (range 2.8 to 25.0+). (For information on the higher incidence of Grade 3 and 4 adverse events, see ADVERSE REACTIONS, Risk Factors Associated with Increased Rates of Adverse Events.)

RETREATMENT, WEEKLY FOR 4 DOSES

In a multi-center, single-arm study, 60 patients received 375 mg/m² of RITUXAN weekly for 4 doses. ¹⁵ All patients had relapsed or refractory, low-grade or follicular B-cell NHL and had achieved an objective clinical response to a prior course of RITUXAN. Of these 60 patients, 55 received their second course of RITUXAN, 3 patients received their third course and 2 patients received their second and third courses of RITUXAN in this study. The ORR was 38% (10% CR and 28% PR) with a projected median duration of response of 15 months (range, 3.0 to 25.1+ months).