A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rituxan Pharmacology, Pharmacokinetics, Studies, Metabolism - Rituximab
Rituxan Pharmacology, Pharmacokinetics, Studies, Metabolism - Rituximab
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
Pre-clinical 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. In
nine patients given 375 mg/m2 as
an IV infusion
for four doses, the mean
serum half-life
was 59.8 hours (range 11.1 to 104.6 hours) after the first infusion
and 174 hours (range 26 to 442 hours) after the fourth infusion.
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.
Rituximab at a dose of
375 mg/m2 was administered as an
IV infusion
at weekly intervals for four doses to 166 patients. 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 to 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 to those with
subtype A. Rituximab was detectable in the serum
of patients three to six months after completion of treatment.
The pharmacokinetic profile
of Rituximab when administered as six infusions of 375 mg/m2
in combination with six cycles of CHOP chemotherapy
was similar to that seen with Rituximab 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. One of the responding
patients (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
six months following completion of treatment. Median B-cell levels
returned to normal by
twelve 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 IgG
and/or IgM serum levels,
resulting in values below the normal
range.
CLINICAL STUDIES
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 four
doses. 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% (80/166)
with a 6% (10/166) complete response
(CR) and a 42% (70/166) partial response
(PR) rate. 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. The median
time to onset of response
was 50 days and the median
duration of response
is projected to be 10 to 12 months.
In a multivariate analysis, the ORR was higher in patients with
IWF B, C, and D histologic subtypes as compared to IWF A subtype
(58% vs. 12%), higher in patients whose largest lesion
was < 5 cm vs. > 7
cm in greatest diameter
(53% vs. 38%), and higher in patients with chemosensitive relapse
as compared to 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 factors were not associated with a lower
response rate: age
60 years, extranodal disease, prior anthracycline
therapy, and bone
marrow involvement.
In a second multicenter, multiple-dose study, 37 patients with
relapsed or refractory
B-cell NHL received 375
mg/m2 of RITUXAN™(Rituximab) as
an IV infusion
once weekly for four doses. 10,11
The ORR was 46% with a median
duration of response
of 8.6 months (range 2.6 to 26.2+). Single doses of up to 500 mg/m2
were well-tolerated. 9
Twenty patients have received two courses and one patient
has received three courses of RITUXAN as four weekly infusions of
375 mg/m2 per infusion. The percentage
of patients reporting adverse events upon retreatment was similar
to that reported following the first course, although the incidence
of specific adverse
events differed (see ADVERSE REACTIONS).
All patients had obtained an objective
clinical response (CR
or PR) to the first course of RITUXAN; upon retreatment, 6 of 12
patients evaluable for response
obtained a complete or partial remission.
Twenty-nine patients with relapsed or refractory, bulky (single
lesion of > 10 cm in diameter),
low grade NHL
received 375 mg/m2 of RITUXAN as
four weekly infusions. The overall incidence
of adverse events and the incidence
of Grade 3 and 4 adverse events was higher in patients with bulky
disease than in patients
with non-bulky disease
(see ADVERSE REACTIONS). Ten
of 21 patients evaluable for response
have obtained a complete or partial remission.
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