Pharmacokinetic behavior of Rituximab: a study of different schedules of administration for heterogeneous clinical settings.

This study was designed to report the pharmacokinetic
behavior of Rituximab in patients affected with different diseases
and treated with different schedules of administration. A low tumor
burden was a common feature of all patients (N = 48) included in our
study, whereas the timing of Rituximab administration varied from
weekly (groups 1, 2, 3) to monthly (group 4). Group 1 included patients
with follicular lymphoma treated with 4 weekly doses of
Rituximab after first-line chemotherapy with CHOP. At the start of
Rituximab, patients were in partial or complete clinical response but
showed persistence of disease at molecular level (bcl-2–positive) in
bone marrow and/or peripheral blood. Patients in group 2 had autoimmune
disorders and Rituximab was given to act on B-cells, interfering
with their production of autoantibodies. In patients with amyloidosis
(group 3), Rituximab was given to kill progenitor B-cells of the small
clone terminating in amyloid-producing plasma cells. In groups 2 and
3, the target of monoclonal antibody was a population of small B
cells, which make an intrinsic feature of the diseases. Group 4 included
patients with relapsed or refractory follicular and mantle cell
lymphoma who underwent a salvage program of immunochemotherapy,
purging in vivo and autotransplant: the first of the six planned
doses of Rituximab was administered after a debulking phase with a
third-generation regimen, such as VACOP-B. An enzyme-linked immunoassay
(ELISA) developed and validated in our laboratory was
used for the pharmacokinetic study. Rituximab disposition was characterized
by a 2-exponential decay, with a long elimination half-life
of approximately 3 weeks (range, 248–859 hours). The total systemic
clearance ranged between 3.1 and 11.9 mL/hr/m2. After 4 weekly infusions,
Rituximab concentration was ;2.5 mg/mL, which is approximately
85% of the steady-state level. Steady-state plasma concentrations
of Rituximab were reached after 6 to 8 weekly infusions. The adopted
pharmacokinetic model (2-compartment open model) seems to provide
the best fit of Rituximab disposition both during and after treatment,
even when different schedules of drug administration are used. Because
several studies reported an association between response and
serum Rituximab concentrations, a treatment based on a pharmacokinetic
model may be useful for predicting the desired drug
concentration.