Rituximab
Introduction to Rituximab
Rituximab (brand names include Rituxan, MabThera) is a chimeric monoclonal antibody targeting CD20, a protein primarily found on the surface of B lymphocytes. It was first approved by the FDA in 1997 for the treatment of certain B-cell non-Hodgkin lymphomas and has since gained approval for various autoimmune conditions. In pediatrics, rituximab is used both on- and off-label for a range of conditions, particularly in rheumatology and hematology.
Mechanism of Action
Rituximab binds specifically to the CD20 antigen expressed on B lymphocytes. Its mechanisms of action include:
- Antibody-dependent cellular cytotoxicity (ADCC)
- Complement-dependent cytotoxicity (CDC)
- Induction of apoptosis in CD20+ cells
- Sensitization of malignant B-cells to chemotherapy
- Inhibition of B-cell activation and proliferation
These mechanisms result in depletion of B lymphocytes, which play a crucial role in various autoimmune diseases and B-cell malignancies.
Indications in Pediatrics
FDA-approved indications:
- Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA):
- Approved for patients 2 years of age and older
- Used in combination with glucocorticoids
Common off-label uses in pediatrics:
- Autoimmune hemolytic anemia (AIHA)
- Immune thrombocytopenia (ITP)
- Systemic lupus erythematosus (SLE)
- Refractory juvenile idiopathic arthritis (JIA)
- Steroid-dependent nephrotic syndrome
- Refractory opsoclonus-myoclonus syndrome
- Pediatric B-cell non-Hodgkin lymphomas
Pharmacokinetics
- Distribution:
- Volume of distribution: 3.1-4.1 L
- Primarily in the vascular compartment
- Metabolism:
- Not extensively metabolized
- Eliminated through cellular uptake followed by catabolism
- Elimination:
- Half-life: 18-32 days (increases with subsequent doses)
- Clearance: 3.1-11.9 mL/h/kg
- Pediatric considerations:
- Clearance and volume of distribution increase with body surface area
- Half-life may be shorter in children compared to adults
Dosage and Administration
Rituximab is administered as an intravenous infusion. Dosing varies based on the indication:
- Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA):
- Induction: 375 mg/m² once weekly for 4 weeks
- Maintenance: Two 250 mg/m² infusions separated by two weeks, then 250 mg/m² every 6 months
- Off-label uses (dosing may vary):
- Typically 375 mg/m² once weekly for 1-4 doses
- Some conditions may require repeated courses
Administration notes:
- Premedicate with acetaminophen and an antihistamine
- Initial infusion rate: 50 mg/hour, increasing gradually if tolerated
- Subsequent infusions may be given at an initial rate of 100 mg/hour
- Do not administer as an IV push or bolus
Side Effects
Common side effects:
- Infusion-related reactions (e.g., fever, chills, rigors)
- Nausea
- Headache
- Fatigue
- Pruritus
Serious side effects:
- Severe infusion reactions
- Tumor lysis syndrome
- Severe mucocutaneous reactions
- Progressive multifocal leukoencephalopathy (PML)
- Hepatitis B virus (HBV) reactivation
- Serious infections
- Cardiovascular events
- Renal toxicity
- Bowel obstruction and perforation
- Cytopenias (neutropenia, thrombocytopenia, anemia)
Monitoring
- Before treatment:
- Screen for hepatitis B virus infection
- Baseline complete blood count
- Assess cardiac function in patients with history of cardiac disease
- During treatment:
- Monitor vital signs during infusions
- Regular complete blood count
- Monitor for signs and symptoms of infection
- Assess for neurological symptoms (potential PML)
- Monitor renal function in patients with renal impairment
- After treatment:
- Monitor B-cell counts
- Continue to monitor for infections (risk may persist for several months)
Drug Interactions
- Live vaccines: Avoid during treatment and until B-cell recovery
- Other immunosuppressants: May increase risk of infections
- Antihypertensive medications: May need dose adjustment due to potential hypotension during infusion
- Cisplatin: May increase risk of renal toxicity
Special Populations
- Pregnancy:
- Category C
- May cause B-cell depletion in the fetus
- Use only if potential benefit justifies potential risk to the fetus
- Lactation:
- Limited data available
- Potential for serious adverse reactions in nursing infants
- Consider developmental and health benefits of breastfeeding along with mother's clinical need for rituximab
- Renal impairment:
- No dose adjustment necessary
- Use with caution; monitor renal function
- Hepatic impairment:
- No formal studies conducted
- Use with caution; monitor liver function
