Source: Health Products Regulatory Authority (ZA) Publisher: Dr. Reddys Laboratories (Pty) Ltd., Block B, 204 Rivonia Road, Morningside, Sandton, 2057
Pharmacological classification: A26 Cytostatic agents
Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies
ATC code: L01XC02
Rituximab is a chimeric monoclonal antibody that recognizes the human CD20 antigen. It is not, however, on haemopoietic stem cells, pro-B cells, normal plasma cells or other normal tissue. The antigen is expressed on >95% of all B cell non Hodgkin Lymphomas (NHLs). This antigen does not internalise upon antibody binding and is not shed from the cell surface. CD20 does not circulate in the plasma as a free antigen and thus, does not compete for antibody binding.
Rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis.
Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC). Rituximab binding to CD 20 antigen on B-lymphocytes has also been demonstrated to induce cell death via apoptosis.
Peripheral B cell counts declined below normal following completion of the first dose of rituximab. In patients treated for haematological malignancies, B cell recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer (up to a median recovery time of 23 months post-induction therapy).
Peripheral blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the majority of patients by week 40, whether rituximab was administered as monotherapy or in combination with methotrexate. A small proportion of patients had prolonged peripheral B cell depletion lasting 2 years or more after their last dose of rituximab.
In Granulomatosis with polyangiitis (Wegener’s) (GPA) and Microscopic polyangiitis (MPA) patients, peripheral blood CD19 B-cells were depleted to less than 10 cells/μl, following the first two infusions of rituximab, and remained at that level in most patients through month 6 timepoint. The majority of patients (81%) showed signs of B cell return, which counts >10 cells/μl by month 12, increasing to 87% by month 18.
Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple infusions of rituximab as a single agent or in combination with CHOP therapy (applied rituximab doses ranged from 100 to 500 mg/m²), the typical population estimates of nonspecific clearance (CL1), specific clearance (CL2) likely contributed by B cells or tumour burden, and central compartment volume of distribution (V1) were 0,14 l/day, 0,59 l/day, and 2,7 l/day, respectively. The estimated median terminal elimination half-life of rituximab was 22 days (range, 6,1 to 52 days). Baseline CD19- positive cell counts and size of measurable tumour lesions contributed to some of the variability in CL2 of rituximab in data from 161 patients given 375 mg/m² as an intravenous infusion for 4 weekly doses.
Patients with higher CD19-positive cell counts or tumour lesions had a higher CL2. However, a large component of inter-individual variability remained for CL2 after correction for CD19-positive cell counts and tumour lesion size. V1 varied by body surface area (BSA) and CHOP therapy. This variability in V1 (27,1% and 19,0%) contributed by the range in BSA (1,53 to 2,32 m²) and concurrent CHOP therapy, respectively, were relatively small. Age, gender, race and WHO performance status had no effect on the pharmacokinetics of rituximab. This analysis suggests that dose adjustment of rituximab with any of the tested covariates is not expected to result in a meaningful reduction in its pharmacokinetic variability.
Rituximab, administered as an intravenous infusion at a dose of 375 mg/m² at weekly intervals for 4 doses to 203 patients with NHL naive to rituximab, yielded a mean Cmax following the fourth infusion of 486 μg/ml (range, 77,5 to 996,6 μg/ml). Rituximab was detectable in the serum of patients 3 to 6 months after completion of last treatment.
Rituximab, administered as an intravenous infusion at a dose of 375 mg/m² at weekly intervals for 4 doses to 203 patients with NHL naive to rituximab, yielded a mean Cmax following the fourth infusion of 486 µg/ml (range, 77,5 to 996,6 µg/ml). Rituximab was detectable in the serum of patients 3 to 6 months after completion of last treatment.
Upon administration of rituximab at a dose of 375 mg/m² as an intravenous infusion at weekly intervals for 8 doses to 37 patients with NHL, the mean Cmax increased with each successive infusion, spanning from a mean of 243 μg/ml (range, 16 to 582 μg/ml) after the first infusion to 550 μg/ml (range, 171 to 1177 μg/ml) after the eighth infusion.
The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m² in combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.
Rituximab was administered as an IV infusion at a first-cycle dose of 375 mg/m² increased to 500 mg/m² each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL patients. The mean Cmax (N=15) was 408 μg/ml (range, 97 to 764 μg/ml) after the fifth 500 mg/m² infusion and the mean terminal half-life was 32 days (range, 14 to 62 days).
Based on the population pharmacokinetic analysis of data in 97 GPA and MPA patients who received 375 mg/m² rituximab once a week for 4 doses, the estimated median terminal elimination half-life was 23 days (range 9 to 49 days). Rituximab mean clearance and volume of distribution were 0,313 l/day (range of 0,116 to 0,726 l/day) and 4,50 l (range of 2,25 to 7,39 l) respectively.
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