Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01X C02 
MabThera subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered substances when administered subcutaneously.

Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on 95 % of all B cell non-Hodgkin’s lymphomas.

CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, pro- B cells, normal plasma cells or other normal tissue. 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.

The Fab domain of 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) mediated by one or more of the Fc receptors on the surface of granulocytes, macrophages and NK cells. 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 MabThera. In patients treated for hematological 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). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg MabThera separated by a 14 day interval. 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 MabThera was administered as monotherapy or in combination with methotrexate.

Clinical experience of MabThera subcutaneous formulation in Non-Hodgkin’s lymphoma 
The clinical experience of MabThera subcutaneous formulation in Non-Hodgkin’s lymphoma is based on data from a phase III clinical trial (SABRINA BO22334) in patients with follicular lymphoma (FL) and a phase Ib dose-finding/dose-confirmation trial (SparkThera BP22333) in patients with FL.
Results from trial BP22333 are presented in section 5.2.

Trial BO22334 (SABRINA)
A two-stage phase III, international, multi-centre, randomised, controlled, open-label trial 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 subcutaneous formulation in combination with CHOP or CVP versus MabThera intravenous formulation in combination with CHOP or CVP.

The objective of the first stage was to establish the rituximab subcutaneous dose that resulted in comparable MabThera subcutaneous formulation serum Ctrough levels compared with MabThera intravenous formulation, when given as part of induction treatment every 3 weeks (see section 5.2).
Stage 1 enrolled previously untreated patients (n=127) CD20-positive, Follicular Lymphoma (FL) Grade 1, 2 or 3a.

The objective of stage 2 was to provide additional efficacy and safety data for subcutaneous rituximab compared with rituximab intravenous using the 1400 mg subcutaneous 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 trial design was identical among both stages and patients were randomized into the following two treatment groups:

•     MabThera subcutaneous formulation (n= 205): first cycle MabThera intravenous formulation plus 7 cycles of MabThera subcutaneous formulation in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks.
MabThera intravenous formulation was used at the standard dose of 375 mg/m2 body surface area.
MabThera subcutaneous formulation was given at a fixed dose of 1400 mg.
Patients achieving at least partial response (PR) were entered on the MabThera subcutaneous formulation maintenance therapy once every 8 weeks for 24 months.
•     MabThera intravenous formulation (n=205): 8 cycles of MabThera intravenous formulation in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks.
MabThera intravenous formulation was used at the standard dose of 375 mg/m2.
Patients achieving at least PR were entered on MabThera intravenous formulation maintenance therapy once every 8 weeks for 24 months.

Key efficacy results for the pooled analysis of 410 patients in SABRINA stages 1 and 2 are shown in table 2.


Table 2        Efficacy results for SABRINA (BO22334) (Intent to Treat Population) 
Pooled Stages 1 & 2
N = 410
Rituximab
Rituximab intravenous subcutaneous formulation formulation
(n = 205)
(n = 205)
Point estimate                           84. 9% (n=174)                         84.4% (n=173) ORRa
95% CI                               [79.2%,89.5%]                          [78.7%,89.1%] 
Point estimate                            31.7% (n=65)                           32.2% (n=66) CRR
95% CI                               [25.4%,38.6%]                          [25.9%,39.1%] 
Proportion with PFS event                        34.6% (n = 71 )                        31.7% ( n = 65) b
PFS
Hazard ratio (95% CI)                                       0.90 [0.64%, 1.26%] ORR – Overall Response Rate
CRR – Complete Response Rate
PFS – Progression-Free Survival (proportion with event, disease progression/relapse or death from any cause) a
– at end of Induction b
– at time of final analysis (median follow-up 58 months)


Exploratory analyses showed response rates among BSA, chemotherapy and gender subgroups were not notably different from the ITT population.

Immunogenicity
Data from the development programme of MabThera subcutaneous formulation indicate that the formation of anti-rituximab antibodies after subcutaneous administration is comparable with that observed after intravenous administration. In the SABRINA trial (BO22334) the incidence of treatment-induced/enhanced anti-rituximab antibodies was low and similar in the intravenous and subcutaneous groups (1.9% vs. 2%, respectively). The incidence of treatment-induced/enhanced anti- rHuPH20 antibodies was 8% in the intravenous group compared with 15% in the subcutaneous 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 antibodies or anti-rHuPH20 antibodies after treatment with MabThera subcutaneous formulation is not known.
There was no apparent impact of the presence of anti-rituximab or anti-rHuPH20 antibodies on safety or efficacy.

Clinical experience of MabThera concentrate for solution for infusion in Non-Hodgkin’s lymphoma Follicular lymphoma


Initial treatment in combination with chemotherapy
In an open-label randomised trial, a total of 322 previously untreated patients with follicular lymphoma were randomised 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 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 analysed 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 vs. 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 significant clinical difference (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 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 trials are summarized in table 3.

Table 3         Summary of key results from four phase III randomized trials evaluating the benefit of MabThera with different chemotherapy regimens in follicular lymphoma Median                              Median               OS
Treatment,                        CR,
Trial                         FU,         ORR, %                  TTF/PFS/ EFS         rates, N                                  % months                              mo                   %
Median TTP:        53-months
CVP, 159                            57        10          14.7               71.1 M39021                                     53                                33.6               80.9 R-CVP, 162                          81        41
P<0.0001          p=0.029

Median TTF: 2.6     18-months
CHOP, 205                                                  years
90        17                             90
GLSG’00            R-CHOP,                 18                             Not reached 96        20                             95
223                                                     p < 0.001         p = 0.016

48-months
Median PFS: 28.8
MCP, 96                             75        25                              74 OSHO-39                                    47                             Not reached R-MCP, 105                          92        50                              87 p < 0.0001 p = 0.0096

CHVP-IFN,                                                                 42-months Median EFS: 36
183                                 85        49                             84 FL2000                                     42                             Not reached R-CHVP-                             94        76                             91 p < 0.0001
IFN, 175                                                                  p = 0.029 
EFS – Event Free Survival
TTP – Time to progression or death
PFS – Progression-Free Survival
TTF – Time to Treatment Failure
OS rates – survival rates at the time of the analyses

Maintenance therapy
Previously untreated follicular lymphoma
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 at 375 mg/m2 body surface area given every 2 months until disease progression or for a maximum period of two years.

The pre-specified primary analysis was conducted at 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 observation in patients with previously untreated follicular lymphoma (Table 4).

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) in the primary analysis (Table 4).

Data from extended follow-up of patients in the study (median follow-up 9 years) confirmed the long- term benefit of MabThera maintenance therapy in terms of PFS, EFS, TNLT and TNCT (Table 4).

Table 4        Overview of efficacy results for MabThera maintenance vs. observation at the protocol-defined primary analysis and after 9 years median follow-up (final analysis)
.
Primary analysis                          Final analysis
(median FU: 25 months)                   (median FU: 9.0 years)
Observation   MabThera                  Observation    MabThera
N=513         N=505                     N=513          N=505
Primary efficacy
Progression-free survival (median)                  NR               NR                 4.06 years      10.49 years log-rank p value                                          <0.0001                                <0.0001 hazard ratio (95% CI)                                 0.50 (0.39, 0.64)                      0.61 (0.52, 0.73) risk reduction                                              50%                                    39% Secondary efficacy
Overall survival (median)                           NR              NR                      NR              NR log-rank p value                                          0.7246                                  0.7948 hazard ratio (95% CI)                                0.89 (0.45, 1.74)                       1.04 (0.77, 1.40) risk reduction                                             11%                                     -6% Event-free survival (median)                    38 months           NR                  4.04 years       9.25 years log-rank p value                                         <0.0001                                 <0.0001 hazard ratio (95% CI)                                0.54 (0.43, 0.69)                       0.64 (0.54, 0.76) risk reduction                                             46%                                     36% TNLT (median)                                      NR               NR                  6.11 years          NR log-rank p value                                          0.0003                                 <0.0001 hazard ratio (95% CI)                                0.61 (0.46, 0.80)                       0.66 (0.55, 0.78) risk reduction                                             39%                                     34% TNCT (median)                                      NR               NR                  9.32 years          NR log-rank p value                                          0.0011                                  0.0004 hazard ratio (95% CI)                                0.60 (0.44, 0.82)                       0.71 (0.59, 0.86) risk reduction                                             40%                                     39% Overall response rate*                             55%              74%                    61%              79% chi-squared test p value                                 <0.0001                                 <0.0001 odds ratio (95% CI)                                  2.33 (1.73, 3.15)                       2.43 (1.84, 3.22) Complete response (CR/CRu) rate*                   48%              67%                    53%              67% chi-squared test p value                                 <0.0001                                 <0.0001 odds ratio (95% CI)                                  2.21 (1.65, 2.94)                       2.34 (1.80, 3.03) * at end of maintenance/observation; final analysis results based on median follow-up of 73 months.
FU: follow-up; NR: not reached at time of clinical cut off, TNCT: time to next chemotherapy treatment; TNLT: time to next anti lymphoma treatment.


MabThera maintenance treatment provided consistent benefit in all predefined 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/CRu or PR). Exploratory analyses of the benefit of maintenance treatment showed a less pronounced effect in elderly patients (> 70 years of age), however sample sizes were small.

Relapsed/Refractory follicular lymphoma
In a prospective, open label, international, multi-centre, phase III trial, 465 patients with relapsed/refractory follicular lymphoma 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 trial. 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 lymphoma when compared to CHOP (see Table 5).

Table 5       Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months median observation time)
CHOP          R-CHOP          p-value   Risk Reduction1)
Primary Efficacy
ORR2)      74 %           87 %          0.0003          Na
CR2)      16 %           29 %          0.0005          Na
PR2)      58 %           58 %          0.9449          Na
1)
Estimates were calculated by hazard ratios
2)
Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend test of CR versus PR versus non-response (p < 0.0001)
Abbreviations: NA, not available; ORR: overall response rate; CR: complete response; PR: partial response 
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 vs. 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 %).


Table 6     Maintenance phase: overview of efficacy results MabThera vs. observation (28 months median observation time)
Efficacy Parameter                Kaplan-Meier Estimate of               Risk Median Time to Event (Months)           Reduction
Observation MabThera        Log-Rank
(N = 167)       (N=167)      p value
Progression-free survival (PFS)    14.3            42.2      < 0.0001         61 % 
Overall Survival                                   NR         NR     0.0039           56 % 
Time to new lymphoma                              20.1        38.8   < 0.0001         50 % treatment

Disease-free survivala                            16.5        53.7   0.0003           67 % 
Subgroup Analysis
PFS
CHOP              11.6        37.5   < 0.0001         71 %
R-CHOP              22.1        51.9    0.0071          46 %
CR              14.3        52.8    0.0008          64 %
PR              14.3        37.8   < 0.0001         54 %

OS
CHOP               NR         NR     0.0348           55 %
R-CHOP               NR         NR     0.0482           56 %

NR: not reached; a : only applicable to patients achieving a CR

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) (table 6). MabThera maintenance treatment significantly prolonged median PFS in patients responding to CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p< 0.0001) as well as in those responding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p=0.0071). Although subgroups were small, MabThera maintenance treatment provided a significant benefit in terms of overall survival for both patients responding to CHOP and patients responding to R-CHOP, although longer follow-up is required to confirm this observation.

Diffuse large B cell non-Hodgkin’s lymphoma

In a randomised, 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 375 mg/m2 plus CHOP (R-CHOP). MabThera was administered on the first day of the treatment cycle.

The final efficacy analysis included all randomised 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 disease characteristics and disease status. The final analysis confirmed that R-CHOP treatment was associated with a clinically relevant and statistically significant improvement in 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 patients subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, β2 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.

Clinical laboratory findings

Of 67 patients evaluated for HAMA, no responses were noted. Of 356 patients evaluated for ADA, 1.1 % (4 patients) were positive.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with rituximab in all subsets of the paediatric population with follicular lymphoma. See Section 4.2 for information on paediatric use.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Rituximab pharmacokinetics following single dose administration of MabThera subcutaneous 375 mg/ m2, 625 mg/ m2 and 800 mg/ m2 were compared with MabThera intravenous 375 mg/ m2 in FL patients. Following subcutaneous administration, the absorption of rituximab is slow, reaching maximal concentrations about 3 days after administration. Based on popPK analysis an absolute bioavailability of 71% was estimated. Rituximab exposure increased dose proportional over the 375 mg/m2 to 800 mg/m2 subcutaneous dose range. Pharmacokinetic parameters such as clearance, distribution volume, and elimination half-life were comparable for both formulations.

Trial BP22333 (SparkThera)
A two-stage phase Ib trial to investigate the pharmacokinetics, safety and tolerability of MabThera subcutaneous formulation in patients with follicular lymphoma (FL) as part of maintenance treatment.
In stage 2, MabThera subcutaneous formulation at a fixed dose of 1400 mg was administered as subcutaneous injection during maintenance treatment, after at least one cycle of MabThera intravenous formulation to FL patients who had previously responded to MabThera intravenous formulation in induction.

The comparison of predicted median Cmax data for MabThera subcutaneous formulation and intravenous formulation are summarized in Table 7.

Table 7: Trial BP22333 (SparkThera): Absorption - Pharmacokinetic parameters of MabThera SC compared to MabThera IV
MabThera       MabThera subcutaneous intravenous
Predicted median Cmax   201            209
(q2m) µg/mL
Predicted median Cmax   189            184
(q3m) µg/mL


The median Tmax in the MabThera subcutaneous formulation was approximately 3 days as compared to the T max occuring at or close to the end of the infusion for the intravenous formulation.

Trial BO22334 (SABRINA)
MabThera subcutaneous formulation at a fixed dose of 1400 mg was administered for 6 cycles subcutaneously during induction at 3-weekly intervals, following the first cycle of MabThera intravenous formulation, in previously untreated FL patients in combination with chemotherapy. The serum rituximab 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 intravenous and the subcutaneous formulations respectively, with the resulting geometric mean ratio (Cmax, SC/Cmax, IV) of 0.941 (90% CI: 0.872, 1.015).

Distribution/Elimination

Geometric mean Ctrough and geometric mean AUCτ from the BP22333 and BO22334 trials are summarized in Table 8.

Table 8: Distribution/Elimination - Pharmacokinetic parameters of MabThera subcutaneous compared to MabThera intravenous
Trial BP22333 (SparkThera)
Geometric      Geometric       Geometric     Geometric mean Ctrough   mean C trough   mean AUCτ     mean AUCτ
(q2m) µg/mL    (q3m) µg/mL     cycle 2 (q2m) cycle 2 (q3m)
µg.day/mL     µg.day/mL
MabThera         32.2           12.1            5430          5320 subcutaneous formulation
MabThera         25.9           10.9            4012          3947 intravenous formulation
Trial BO22334 (SABRINA)
Geometric mean                      Geometric mean
Ctrough values at pre-dose cycle 8 AUC values at cycle 7
µg/mL                               µg.day/mL
MabThera          134.6                               3778 subcutaneous formulation
MabThera          83.1                                2734 intravenous formulation
In a population pharmacokinetic analysis in 403 follicular lymphoma patients who received subcutaneous and/or intravenous MabThera, 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/day, respectively.
The estimated median terminal elimination half-life of MabThera subcutaneous formulation was 29.7 days (range, 9.9 to 91.2 days).The analysis data set contained 6003 quantifiable samples from 403 patients administered SC and/or IV rituximab in trials BP22333 (3736 samples from 277 patients) and BO22334 (2267 samples from126 patients). Twenty nine (0.48%) post-dose observations (all from trial BP22333) were below the quantification limit. There were no missing covariate values except baseline B-cell count. Baseline tumour load was available only in trial BO22334.

Special populations

In clinical trial BO22334, an effect was observed between body size and exposure ratios reported in cycle 7, between rituximab subcutaneous formulation 1400 mg q3w and rituximab intravenous 
formulation 375 mg/m2 q3w with C trough ratios of 2.29, 1.31, and 1.41 in patients with low, medium and high BSA, respectively (low BSA  1.70 m2; 1.70 m2 < medium BSA < 1.90 m2; high BSA  1.90 m2). The corresponding AUCτ ratios were 1.66, 1.17 and 1.32.

There was no evidence of clinically relevant dependencies of rituximab pharmacokinetics on age and sex.

Anti-rituximab antibodies were detected in only 13 patients and did not result in any clinically relevant increase in steady-state clearance.