Antineoplastic agent. ATC Code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Rituximab is a chimeric mouse/human monoclonal antibody that binds specifically to the transmembrane antigen CD20. This antigen is located on pre-B- and mature B-lymphocytes, but not on hemopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue. The antigen is expressed on >95% of all B-cell non-Hodgkin's lymphomas (NHLs). Following antibody binding, CD20 is not internalized or shed from the cell membrane into the environment. 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 initiates immunologic reactions that mediate B-cell lysis. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. Finally, in vitro studies have demonstrated that rituximab sensitizes drug-resistant human B-cell lymphoma lines to the cytotoxic effects of some chemotherapeutic agents.
Peripheral B-cell counts declined to levels below normal following the first dose of MabThera. In patients treated for hematological malignancies, B cell recovery began within 6 months of treatment and generally returning to normal levels within 12 months after completion of therapy, although in some patients this may take longer (see Adverse Reactions). In patients with rheumatoid arthritis, the duration of peripheral B cell depletion was variable. The majority of patients received further treatment prior to full B cell repletion. A small proportion of patients had prolonged peripheral B cell depletion lasting 2 years or more after their last dose of MabThera IV.
In GPA and MPA patients, peripheral blood CD19 B-cells 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.
Of 67 patients evaluated for human anti-mouse antibody (HAMA), none were positive. Of 356 non-Hodgkin's lymphoma patients evaluated for human anti-chimeric antibody (HACA) 1.1% (4 patients) were positive.
Low-grade or follicular non-Hodgkin's lymphoma: Monotherapy: Initial treatment, weekly for 4 doses: In the pivotal study, 166 patients with relapsed or chemoresistant low-grade or follicular B-cell NHL received 375 mg/m2
of MabThera as an IV infusion weekly for four doses. The overall response rate (ORR) in the intent-to-treat (ITT) population was 48% (CI95%
41%-56%) with a 6% complete response (CR) and a 42% partial response (PR) rate. The projected median time to progression (TTP) for responding patients was 13.0 months.
In a subgroup analysis, the ORR was higher in patients with IWF B, C, and D histologic subtypes as compared to IWF A subtype (58% versus 12%), higher in patients whose largest lesion was <5 cm versus >7 cm in greatest diameter (53% versus 38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration of response <3 months) relapse (50% versus 22%). ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT. Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or high LDH nor presence of extranodal disease had a statistically significant effect (Fisher's exact test) on response to MabThera.
A statistically significant correlation was noted between response rates and bone marrow involvement. 40% of patients with bone marrow involvement responded compared to 59% of patients with no bone marrow involvement (p=0.0186). This finding was not supported by a stepwise logistic regression analysis in which the following factors were identified as prognostic factors: histologic type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky disease.
Initial treatment, weekly for 8 doses: In a multi-center, single-arm study, 37 patients with relapsed or chemoresistant, low grade or follicular B-cell NHL received 375 mg/m2
of MabThera as IV infusion weekly for eight doses. The ORR was 57% (CI95%
41%-73%; CR 14%, PR 43%) with a projected median TTP for responding patients of 19.4 months (range 5.3 to 38.9 months).
Initial treatment, bulky disease, weekly for 4 doses: In pooled data from three studies, 39 patients with relapsed or chemoresistant, bulky disease (single lesion ≥10 cm in diameter), low grade or follicular B-cell NHL received 375 mg/m2
of MabThera as IV infusion weekly for four doses. The ORR was 36% (CI95%
21%-51%; CR 3%, PR 33%) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).
Re-treatment, weekly for 4 doses: In a multi-center, single-arm study, 58 patients with relapsed or chemoresistant low grade or follicular B-cell NHL, who had achieved an objective clinical response to a prior course of MabThera, were re-treated with 375 mg/m2
of MabThera as i.v. infusion weekly for four doses. Three of the patients had received two courses of MabThera before enrollment and thus were given a third course in the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the ORR was 38% (CI95%
26%-51%; 10% CR, 28% PR) with a projected median TTP for responding patients of 17.8 months (range 5.4-26.6). This compares favorably with the TTP achieved after the prior course of MabThera (12.4 months).
In combination with chemotherapy: Initial treatment: In an open-label randomized trial, a total of 322 previously untreated patients with follicular lymphoma were randomized to receive either CVP chemotherapy (cyclophosphamide 750 mg/m2
, vincristine 1.4 mg/m2
up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2
/day on days 1-5) every 3 weeks for 8 cycles or MabThera IV 375 mg/m2
in combination with CVP (R-CVP). MabThera was administered on the first day of each treatment cycle. A total of 321 patients (162 R-CVP, 159 CVP) received therapy and were analyzed for efficacy.
The median follow-up of patients was 53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatment failure (27 months versus 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumour response (CR, CRu, PR) was significantly higher (p< 0.0001 Chi-Square test) in the R-CVP group (80.9%) than the CVP group (57.2%). Treatment with R-CVP significantly prolonged the time to disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively (p < 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p < 0.0001, log-rank test). The difference between the treatment groups with respect to overall survival showed a strong clinical benefit (p=0.029, log-rank test stratified by center): survival rates at 53 months were 80.9% for patients in the R-CVP group compared to 71.1% for patients in the CVP group.
Results from three other randomized trials using MabThera IV in combination with chemotherapy regimen other than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant improvements in response rates, time-dependent parameters as well as in overall survival. Key results from all four studies are summarized in Table 1 as follows. (See Table 1.)
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Maintenance therapy: Previously untreated follicular NHL: In a prospective, open label, international, multi-center, phase III trial 1193 patients with previously untreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP (n=268) or R-FCM (n=44), according to the investigators' choice. A total of 1078 patients responded to induction therapy, of which 1018 were randomized to MabThera maintenance therapy (n=505) or observation (n=513). The two treatment groups were well balanced with regards to baseline characteristics and disease status. MabThera maintenance treatment consisted of a single infusion of MabThera IV at 375 mg/m2
body surface area given every 2 months until disease progression or for a maximum period of two years.
After a median observation time of 25 months from randomization, maintenance therapy with MabThera resulted in a clinically relevant and statistically significant improvement in the primary endpoint of investigator assessed progression-free survival (PFS) as compared to no maintenance therapy in patients with previously untreated follicular NHL (see Table 2). This improvement in PFS was confirmed by an independent review committee (IRC) (see Table 2).
Significant benefit from maintenance treatment with MabThera was also seen for the secondary endpoints event-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to next chemotherapy (TNCT) and overall response rate (ORR) (see Table 2).
The updated analysis corresponding to a median observation time of 73 months from randomization confirm the results of the primary analysis. (See Table 2.)
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MabThera maintenance treatment provided consistent benefit in all subgroups tested: gender (male, female), age (<60 years, >=60 years), FLIPI score (1, 2 or 3), induction therapy (R-CHOP, R-CVP or R-FCM) and regardless of the quality of response to induction treatment (CR or PR).
Relapsed/Refractory follicular NHL: In a prospective, open label, international, multi-centre, phase III trial, 465 patients with relapsed/refractory follicular NHL were randomised in a first step to induction therapy with either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or MabThera plus CHOP (R-CHOP, n=234). The two treatment groups were well balanced with regard to baseline characteristics and disease status. A total of 334 patients achieving a complete or partial remission following induction therapy were randomised in a second step to MabThera maintenance therapy (n=167) or observation (n=167). MabThera maintenance treatment consisted of a single infusion of MabThera at 375 mg/m2
body surface area given every 3 months until disease progression or for a maximum period of two years.
The final efficacy analysis included all patients randomized to both parts of the study. After a median observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly improved the outcome of patients with relapsed/refractory follicular NHL when compared to CHOP (see Table 3).
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For patients randomized to the maintenance phase of the trial, the median observation time was 28 months from maintenance randomisation. Maintenance treatment with MabThera led to a clinically relevant and statistically significant improvement in the primary endpoint, PFS, (time from maintenance randomisation to relapse, disease progression or death) when compared to observation alone (p<0.0001 log-rank test). The median PFS was 42.2 months in the MabThera maintenance arm compared to 14.3 months in the observation arm. Using a cox regression analysis, the risk of experiencing progressive disease or death was reduced by 61% with MabThera maintenance treatment when compared to observation (95% CI; 45%-72%). Kaplan-Meier estimated progression-free rates at 12 months were 78% in the MabThera maintenance group versus 57% in the observation group. An analysis of overall survival confirmed the significant benefit of MabThera maintenance over observation (p=0.0039 log-rank test). MabThera maintenance treatment reduced the risk of death by 56% (95% CI; 22%-75%).
The median time to new anti-lymphoma treatment was significantly longer with MabThera maintenance treatment than with observation (38.8 months versus. 20.1 months, p<0.0001 log-rank test). The risk of starting a new treatment was reduced by 50% (95% CI; 30%-64%). In patients achieving a CR/CRu (complete response unconfirmed) as best response during induction treatment, MabThera maintenance treatment significantly prolonged the median disease free survival (DFS) compared to the observation group (53.7 versus 16.5 months, p=0.0003) log-rank test (Table 4). The risk of relapse in complete responders was reduced by 67% (95% CI; 39%-82%). (See Table 4.)
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The benefit of MabThera maintenance treatment was confirmed in all subgroups analysed, regardless of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) (see Table 4). MabThera maintenance treatment significantly prolonged median PFS in patients responding to CHOP induction therapy (median PFS 37.5 months versus 11.6 months, p<0.0001) as well as in those responding to R-CHOP induction (median PFS 51.9 months versus 22.1 months, p=0.0071). MabThera maintenance treatment also provided a clinically meaningful benefit in terms of overall survival for both patients responding to CHOP and patients responding to R-CHOP in the induction phase of the study.
MabThera maintenance treatment provided consistent benefit in all subgroups tested [gender, age (≤60 years, > 60 years), stage (III, IV), WHO performance status (0 versus >0), B symptoms (absent, present), bone marrow involvement (no versus yes), IPI (0-2 versus 3-5), FLIPI score (0-1, versus 2 versus 3-5), number of extra-nodal sites (0-1 versus >1), number of nodal sites (<5 versus ≥5), number of previous regimens (1 versus 2), best response to prior therapy (CR/PR versus NC/PD), hemoglobin (<12 g/dL versus ≥12 g/dL), β2
-microglobulin (< 3mg/L versus ≥3 mg/L), LDH (elevated, not elevated) except for the small subgroup of patients with bulky disease.
Diffuse large B-cell non-Hodgkin's lymphoma: In a randomized, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80 years) with diffuse large B-cell lymphoma received standard CHOP chemotherapy (cyclophosphamide 750 mg/m2
, doxorubicin 50 mg/m2
, vincristine 1.4 mg/m2
up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2
/day on days 1 - 5) every 3 weeks for eight cycles, or MabThera IV 375 mg/m2
plus CHOP (R-CHOP). MabThera was administered on the first day of the treatment cycle.
The final efficacy analysis included all randomized patients (197 CHOP, 202 R-CHOP), and had a median follow-up duration of approximately 31 months. The two treatment groups were well balanced in baseline characteristics and disease status. The final analysis confirmed that R-CHOP significantly increased the duration of event-free survival (the primary efficacy parameter, where events were death, relapse or progression of lymphoma, or institution of a new anti-lymphoma treatment) (p=0.0001). Kaplan Meier estimates of the median duration of event-free survival were 35 months in the R-CHOP arm compared to 13 months in the CHOP arm, representing a risk reduction of 41%. At 24 months, estimates for overall survival were 68.2% in the R-CHOP arm compared to 57.4% in the CHOP arm. A subsequent analysis of the duration of overall survival, carried out with a median follow-up duration of 60 months, confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071), representing a risk reduction of 32%.
The analysis of all secondary parameters (response rates, progression-free survival, disease-free survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The complete response rate after cycle 8 was 76.2% in the R-CHOP group and 62.4% in the CHOP group (p=0.0028). The risk of disease progression was reduced by 46% and the risk of relapse by 51%.
In all patient subgroups (gender, age, age-adjusted IPI, Ann Arbor stage, ECOG, Beta 2 Microglobulin, LDH, Albumin, B-symptoms, Bulky disease, extranodal sites, bone marrow involvement), the risk ratios for event-free survival and overall survival (R-CHOP compared with CHOP) were less than 0.83 and 0.95; respectively. R-CHOP was associated with improvements in outcome for both high- and low-risk patients according to age-adjusted IPI.
Subcutaneous formulation: Previously untreated Follicular Non-Hodgkin's Lymphoma BO22334 (SABRINA): A two-stage phase III, international, multi-center, randomized, controlled, open-label study was conducted in patients with previously untreated follicular lymphoma, to investigate the non-inferiority of the pharmacokinetic profile, together with efficacy and safety of MabThera SC in combination with CHOP or CVP versus MabThera IV in combination with CHOP or CVP followed by MabThera /Rituxan maintenance therapy.
The objective of the first stage was to establish the rituximab SC dose that resulted in comparable MabThera serum Ctrough
levels compared with MabThera IV, when given as part of induction treatment every 3 weeks (see Pharmacology: Pharmacokinetics: Distribution under Actions). Stage 1 enrolled previously untreated patients (n=127) with CD20-positive, Follicular Lymphoma (FL) Grade 1, 2 or 3a.
The objective of stage 2 was to provide additional efficacy and safety data for rituximab SC compared with rituximab IV using the 1400 mg SC dose established in stage 1. Previously untreated patients with CD20-positive, Follicular Lymphoma Grade 1, 2 or 3a (n=283) were enrolled in the stage 2.
The overall study design was identical among both stages and patients were randomized into the following two treatment groups: MabThera SC (n=205): 1st cycle MabThera IV plus 7 cycles of MabThera SC in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. IV MabThera was used at the standard dose of 375 mg/m2
. MabThera SC was given at a dose of 1400 mg. Patients achieving at least PR were entered on the MabThera SC maintenance therapy once every 8 weeks for 24 months.
MabThera IV (n=205): 8 cycles of MabThera IV in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. IV MabThera was used at the standard dose of 375 mg/m2
. Patients achieving at least PR were entered on MabThera IV maintenance therapy once every 8 weeks for 24 months.
In the pooled analysis of 410 patients the overall response rate point estimates were 84.4% (95% CI: 78.7; 89.1) and 83.4% (95% CI: 77.6; 88.2) in the MabThera IV and SC arms, respectively. Complete response rate point estimates were 31.7% (95% CI: 25.4; 38.6) and 32.7% (95% CI: 26.3; 39.6) in the MabThera IV and SC arms, respectively. Exploratory analyses showed response rates among BSA, chemotherapy and gender subgroups were not notably different from the ITT population.
Data from the SC development program indicate that the formation of anti-rituximab antibodies (HACAs) after SC administration is comparable with that observed after IV administration. In SABRINA study (BO22334) the incidence of treatment-induced/enhanced anti-rituximab antibodies in the SC group was low and similar to that observed in the IV group (1% IV versus 2% SC). The incidence of treatment-induced/enhanced anti-rHuPH20 antibodies was 6% in the IV group compared with 9% in the SC group, and none of the patients who tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies. The overall proportion of patients found to have anti-rHuPH20 antibodies remained generally constant over the follow-up period in both cohorts.
The clinical relevance of the development of anti-rituximab or anti-rHuPH20 antibodies after treatment with MabThera SC is not known. There was no impact of the presence of anti-rituximab or anti-rHuPH20 antibodies on safety or efficacy in both studies.
Subcutaneous Formulation for Non-Hodgkin's Lymphoma: MabThera at a fixed dose of 1400 mg was administered as a single injection SC during maintenance, after at least one cycle of MabThera IV, in FL patients who had previously responded to MabThera IV in induction. The predicted median Cmax
for administered every two months (q2m) MabThera SC and for q2m MabThera IV respectively were comparable at 201 and 209 μg/mL. Similarly for q3m MabThera SC and q3m MabThera IV respectively the predicted median Cmax were comparable at 189 and 184 μg/mL. The median Ttmax
in the MabThera SC was approximately 3 days as compared to the Ttmax
occuring at or close to the end of the infusion for the MabThera IV.
MabThera at a fixed dose of 1400 mg was administered for 6 cycles SC during induction at 3-weekly intervals, following the first cycle of MabThera IV, in previously untreated FL patients in combination with chemotherapy. The serum MabThera Cmax at Cycle 7 was similar between the two treatment arms, with geometric mean (CV%) values of 250.63 (19.01) μg/mL and 236.82 (29.41) μg/mL for the MabThera IV and the MabThera SC, respectively with the resulting geometric mean ratio (Cmax, SC/Cmax, IV) of 0.941 (90% CI: 0.872, 1.015).
Based on a population pharmacokinetic analysis, an absolute bioavailability of 71% (95%CI: 70.0 – 72.1) was estimated.
Non-Hodgkin's Lymphoma: Intravenous Formulation: Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple infusions of MabThera as a single agent or in combination with CHOP therapy, 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, 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 i.v. 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.
MabThera at a dose of 375 mg/m2
was administered as an i.v. infusion at weekly intervals for 4 doses to 203 patients with NHL naive to Rituximab. The mean Cmax
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 CD19-positive B-cells and measures of disease burden. Median steady-state serum levels were higher for responders compared with non-responders. 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 3-6 months after completion of last treatment.
MabThera at a dose of 375 mg/m2
was administered as an i.v. 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, 16-582 μg/mL) after the first infusion to 550 μg/mL (range, 171-1177 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.
Subcutaneous Formulation: SparkThera (BP22333): MabThera at a fixed dose of 1400 mg was administered as a single injection SC during maintenance, after at least one cycle of rituximab IV, in FL patients who had previously responded to MabThera IV in induction. The predicted mean and geometric mean Ctrough values at cycle 2 were higher in the MabThera SC group than the MabThera IV group. The geometric mean values for q2m MabThera SC and q2m MabThera IV respectively were 32.2 and 25.9 μg/mL and for q3m MabThera SC and q3m MabThera IV respectively were 12.1 and 10.9 μg/mL. Similarly, the predicted mean and geometric mean AUCtau values at cycle 2 were higher in the MabThera SC group than the MabThera IV group. The geometric mean for q2m MabThera SC and q2m MabThera IV respectively were 5430 and 4012 μg·day/mL and for q3m MabThera SC and q3m MabThera IV respectively were 5320 and 3947 μg·day/mL.
SABRINA (BO22334): MabThera at a fixed dose of 1400 mg was administered as a SC injection, in the abdomen, at 3-weekly intervals. Previously untreated patients with CD20+ FL Grade 1, 2, or 3a were randomized 1:1 to receive MabThera SC (first cycle rituximab IV followed by 7 cycles of rituximab SC) or MabThera IV (8 cycles) in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every three weeks as part of induction treatment. The mean and geometric mean Ctrough values at pre-dose Cycle 8 were higher among the MabThera SC group than the MabThera IV group. The geometric mean was 134.6 μg/mL for the MabThera SC group compared with 83.1 μg/mL for the MabThera IV group.
Similarly, the mean and geometric mean AUC values at Cycle 7 were higher among the MabThera SC group than the MabThera IV group. The geometric mean AUC was 3778 μg·day/mL for the MabThera SC group compared with 2733 μg·day/mL for the r MabThera IV group.
In a population pharmacokinetic analysis in FL patients who received single or multiple infusions of MabThera as a single agent or in combination with chemotherapy, the population estimates of nonspecific clearance (CL1), initial specific clearance (CL2) (likely contributed by B cells or tumour burden) and central compartment volume of distribution (V1) were 0.194 L/day, 0.535 L/day, and 4.37 L, respectively. The estimated median terminal elimination half-life of MabThera SC was 29.7 days (range, 9.9 to 91.2 days).
In the final analysis dataset from 403 patients administered SC and/or IV MabThera in studies BP22333 (277 patients) and BO22334 (126 patients) the mean (range) weight and body surface area were 74.4 kg (43.9 to 130 kg) and 1.83 m2
(1.34 to 2.48 m2
), respectively. Mean (range) age was 57.4 years (23 to 87 years). There were no differences between demographic and laboratory parameters of the two studies. However, the baseline B-cell counts were markedly lower in Study BP22333, than in Study BO22334, as patients in Study BP22333 entered the study having received a minimum of four cycles of MabThera IV in induction and at least one cycle of MabThera IV maintenance, whereas patients in Study BO22334 had not received MabThera prior to study enrollment. Data on baseline tumour load was available only for patients in Study BO22334.
BSA was identified as the main covariate. All clearance and volume parameters increased with the body size. Among other covariate dependencies, central volume increased with age and the absorption rate constant decreased with age (for patients aged > 60 years), but these age dependencies were shown to result in negligible changes in MabThera exposure. Anti-drug antibodies were detected in only 13 patients and did not result in any clinically relevant increase in clearance.
Chronic Lymphocytic Leukaemia: Intravenous Formulation: MabThera was administered as an i.v 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, 97-764 μg/mL) after the fifth 500 mg/m2
Rheumatoid Arthritis: Following two intravenous infusions of rituximab at a dose of 1000 mg, two weeks apart, the mean terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day (range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 L (range, 1.7 to 7.51 L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis revealed that BSA and gender were the most significant covariates to explain inter-individual variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic differences are not considered to be clinically relevant and dose adjustment is not required. The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were dose proportional over the limited dose range studied. Mean Cmax
for serum rituximab following first infusion ranged from 157 to 171 μg/mL for 2 x 500 mg dose and ranged from 298 to 341 μg/mL for 2 x 1000 mg dose. Following second infusion, mean Cmax
ranged from 183 to 198 μg/mL for the 2 x 500 mg dose and ranged from 355 to 404 μg/mL for the 2 x 1000 mg dose. Mean terminal elimination half-life ranged from 15 to 16.5 days for the 2 x 500 mg dose group and 17 to 21 days for the 2 x 1000 mg dose group. Mean Cmax
was 16 to 19% higher following second infusion compared to the first infusion for both doses. The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg upon re-treatment in the second course. Mean Cmax
for serum rituximab following first infusion was 170 to 175 μg/mL for 2 x 500 mg dose and 317 to 370 μg/mL for 2 x 1000 mg dose. Cmax
following second infusion, was 207 μg/mL for the 2 x 500 mg dose and ranged from 377 to 386 μg/mL for the 2 x 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second course, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 days for the 2 x 1000 mg dose. PK parameters for rituximab were comparable over the two treatment courses. The pharmacokinetic parameters in the anti-TNF inadequate responder population, following the same dosage regimen (2 x 1000 mg, i.v., 2 weeks apart), were similar with a mean maximum serum concentration of 369 μg/mL and a mean terminal half-life of 19.2 days.
Granulomatosis with polyangiitis (Wegener's) (GPA) and Microscopic polyangiitis (MPA): Based on the population pharmacokinetic analysis of data in 97 GPA and MPA patients who received 375 mg/m2
rituximab once weekly for four 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, 0.116 to 0.726 L/day) and 4.50 L (range 2.25 to 7.39 L) respectively. The PK parameters of rituximab in GPA and MPA patients appear similar to what has been observed in RA patients (see section above).
Pharmacokinetics in Special Populations:
No pharmacokinetic data are available in patients with hepatic or renal impairment.
Toxicology: Preclinical Safety:
Other: Subcutaneous Formulation: The subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. Systemic absorption of rHuPH20 after subcutaneous administration is unlikely to occur. However, pharmacokinetic and toxicology studies in animals demonstrate reductions in foetal weight and increases in the number of resorptions following injection of rHuPH20, at maternal systemic exposure levels comparable to those that could occur after accidental bolus IV administration of a single vial of the MabThera SC formulation in humans, based on the most conservative assumptions possible. There is no evidence of dysmorphogenesis (i.e. teratogenesis) resulting from systemic exposure to rHuPH20.