DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 62–2
Dose and Toxicity of Monoclonal Antibody–Based Drugs
DRUG MECHANISM DOSE AND SCHEDULE MAJOR TOXICITY
Rituximab ADCC; CDC; apoptosis 375-mg/m 2 IV infusion Infusion-related toxicity
weekly for 4 weeks with fever, rash, and dyspnea;
B-cell depletion; late-onset
neutropenia
Alemtuzumab ADCC; CDC; apoptosis Escalating doses of 3, 10, Infusion-related toxicity,
30 mg/m 2 IV three times/ T-cell depletion
week followed by
with increased infection;
30 mg/m 2 three times/week hematopoietic suppression;
for 4-12 weeks
pancytopenia
Trastuzumab ADCC; apoptosis; Loading dose of 4-mg/kg Cardiomyopathy;
inhibition of arrest infusion followed by infusion-related toxicity
HER2 signaling
2 mg/kg weekly
with G 1
arrest
Cetuximab Inhibition of EGFR Loading dose of 400-mg/kg Infusion-related toxicity;
signaling; apoptosis; infusion followed by skin rash in 75%
ADCC
250 mg/kg weekly
Bevacizumab Inhibition of 5 mg/kg IV every 14 days Hypertension; pulmonary
angiogenesis/ until disease hemorrhage; GI
neovascularization progression perforation; proteinuria;
congestive heart failure
Denileukin diftitox Targeted diphtheria 9-18 μg/kg/day IV for the Fever; arthralgia; asthenia;
toxin with inhibition first 5 days every 3 weeks hypotension
of protein synthesis
Gemtuzumab Double-strand DNA Two doses of 9 mg/m 2 IV Infusion-related toxicity;
ozogamicin breaks and apoptosis separated by 14 days hematopoietic suppression;
mucosal hepatic (VOD);
skin toxicity
90
Y-ibritumomab Targeted radiotherapy 0.4 mCi/kg IV Hematological toxicity;
tiuxetan
myelodysplasia
131
I-tositumomab Targeted radiotherapy Patient-specific Hematological toxicity;
dosimetry
myelodysplasia
ADCC, antibody-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; EGFR, epidermal growth factor receptor; intravenous;
VOD, veno-occlusive disease.
of treatment, and patients should receive standard tumor lysis prophylaxis.
The remainder of the dose can then be given on day 3.
Resistance and Toxicity. Resistance to rituximab may emerge
through downregulation of CD20, impaired antibody-dependent cellular
cytotoxicity, decreased complement activation, limited effects
on signaling and induction of apoptosis, and inadequate blood levels
(Maloney et al., 2002). Polymorphisms in two of the receptors for
the antibody Fc region responsible for complement activation, Fcγ
RIIIa and Fcγ RIIa, may predict the clinical response to rituximab
monotherapy in patients with follicular lymphoma but not in CLL
(Cartron et al., 2002).
Rituximab infusional reactions can be life-threatening, but
with pretreatment are usually mild and limited to fever, chills, throat
itching, urticaria, and mild hypotension. All respond to decreased
infusion rates and antihistamines. Uncommonly, patients may
develop severe mucocutaneous skin reactions, including Stevens-
Johnson syndrome. Rituximab may cause reactivation of hepatitis B
virus or rarely, JC virus (with progressive multifocal leukoencephalopathy)
(Kranick et al., 2007). Patients should be screened for
hepatitis B before initiation of therapy. Hypogammaglobulinemia
and autoimmune syndromes (idiopathic thrombocytopenic purpura,
thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia,
pure red cell aplasia, and delayed neutropenia) may supervene
1-5 months after administration (Cattaneo et al., 2006).
Ofatumumab. Ofatumumab (ARZERRA) is a second
monoclonal antibody that binds to CD20 at sites on the
major and minor extracellular loops of CD20, distinct