Usage
Brentuximab vedotin is prescribed for the treatment of certain types of lymphomas. These include:
- Classical Hodgkin Lymphoma (cHL): In adults, it is used in combination with chemotherapy for previously untreated stage III or IV cHL, consolidation therapy after autologous stem cell transplant (ASCT), and for relapsed or refractory cHL after ASCT or at least two prior multi-agent chemotherapy regimens. In pediatric patients, it’s used in combination with chemotherapy for previously untreated high-risk cHL.
- Systemic Anaplastic Large Cell Lymphoma (sALCL): In adults, it is used for relapsed or refractory sALCL and in combination with chemotherapy for previously untreated sALCL.
- Other CD30-expressing Peripheral T-cell Lymphomas (PTCL): Used in combination with chemotherapy for previously untreated cases.
- Cutaneous T-cell lymphoma (CTCL): Specifically, CD30-expressing Mycosis Fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL), after at least one prior systemic therapy.
Brentuximab vedotin is classified as an anti-neoplastic agent, specifically an antibody-drug conjugate (ADC). It combines a monoclonal antibody targeting the CD30 protein with the anti-microtubule agent monomethyl auristatin E (MMAE). This ADC selectively delivers the cytotoxic agent to CD30-expressing tumor cells, minimizing systemic toxicity.
Alternate Names
Brentuximab vedotin is also marketed under the brand name Adcetris.
How It Works
Pharmacodynamics: Brentuximab vedotin binds specifically to the CD30 antigen expressed on the surface of lymphoma cells. Following internalization, the linker connecting the antibody and MMAE is cleaved, releasing MMAE inside the cell. MMAE inhibits cell division by disrupting microtubule formation, leading to cell cycle arrest and apoptosis (programmed cell death) of the targeted cancer cells.
Pharmacokinetics:
- Absorption: Brentuximab vedotin is administered intravenously.
- Metabolism: The metabolism is thought to predominantly involve proteolytic cleavage to release MMAE. CYP3A4 enzymes are involved in MMAE metabolism, but brentuximab vedotin is not expected to alter the exposure to medicines metabolized by CYP3A4.
- Elimination: Primarily eliminated by metabolism, renal, and hepatic routes.
Mode of Action: Brentuximab vedotin targets and binds to the CD30 receptor. It is internalized into the cell where MMAE, the cytotoxic component, is released after proteolytic cleavage of the linker. MMAE inhibits microtubule polymerization by binding to tubulin, causing cell cycle arrest at the G2/M phase, and ultimately inducing apoptosis. Brentuximab vedotin does not involve enzyme inhibition or neurotransmitter modulation in its primary mechanism. Elimination pathways involve both renal and hepatic excretion.
Dosage
Standard Dosage
Adults:
The standard dose is 1.8 mg/kg (up to a maximum of 180 mg in patients >100kg), administered as an intravenous infusion over 30 minutes every 3 weeks. Dosing varies depending on the specific lymphoma and treatment regimen. Lower doses (e.g., 1.2 mg/kg) may be used in combination regimens or in patients with specific toxicities. Maximum dose per cycle, for patients >100kg is capped at 180 mg for a dosage of 1.8mg/kg or 120 mg for dosage of 1.2 mg/kg. The duration of treatment is until disease progression or unacceptable toxicity. Consolidation therapy after ASCT is recommended to start within 4-6 weeks post-ASCT or after recovery and is given for up to 16 cycles.
Children:
For pediatric patients with high-risk cHL (2 years and older), the recommended dose is 1.8 mg/kg (up to a maximum of 180 mg) IV every 3 weeks (in combination with AVE-PC). Safety and efficacy in children younger than 2 years have not been established.
Special Cases:
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Elderly Patients: No specific dose adjustment is recommended, but closer monitoring is warranted due to potential increased sensitivity to side effects.
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Patients with Renal Impairment: No dose adjustment for mild or moderate renal impairment. Avoid use in patients with severe renal impairment (CrCl <30 mL/min).
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Patients with Hepatic Dysfunction: A starting dose of 1.2 mg/kg every 3 weeks is recommended for patients with mild hepatic impairment. Avoid use in patients with moderate or severe hepatic impairment.
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Patients with Comorbid Conditions: Dosage adjustments may be needed depending on specific comorbid conditions and should be considered on a case-by-case basis.
Clinical Use Cases
Brentuximab vedotin is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its usage is specifically limited to the cancer types previously listed.
Dosage Adjustments
Dose modifications, including delays, reductions, or discontinuation, may be required based on individual patient tolerance and adverse events, especially peripheral neuropathy and neutropenia. Specific guidance on dosage adjustments for toxicity is outlined in the full prescribing information.
Side Effects
Common Side Effects
Peripheral neuropathy (numbness, tingling, pain), fatigue, nausea, diarrhea, neutropenia, anemia, thrombocytopenia, constipation, fever, infections (including upper respiratory tract infections).
Rare but Serious Side Effects
Progressive multifocal leukoencephalopathy (PML), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), tumor lysis syndrome, severe anemia, thrombocytopenia, neutropenia (with or without fever), anaphylaxis/infusion reactions, pulmonary toxicity (pneumonitis, interstitial lung disease, acute respiratory distress syndrome), Guillain-Barré syndrome, peripheral motor neuropathy.
Long-Term Effects
Peripheral neuropathy can be persistent and long-lasting even after treatment discontinuation.
Adverse Drug Reactions (ADR)
Any severe or life-threatening side effects, such as PML, anaphylaxis, SJS/TEN, should be considered adverse drug reactions requiring immediate intervention.
Contraindications
- Concomitant use with bleomycin due to increased risk of pulmonary toxicity.
- Hypersensitivity to brentuximab vedotin or its components.
Drug Interactions
- CYP3A4 inhibitors: Co-administration with strong CYP3A4 inhibitors may increase exposure to MMAE, potentially increasing toxicity.
- P-glycoprotein (P-gp) inhibitors/inducers: Concomitant use of P-gp inhibitors may increase, and P-gp inducers may decrease brentuximab vedotin exposure.
- Other Interactions: Concurrent use with other myelosuppressive agents or neurotoxic agents may exacerbate side effects. Several other interactions can occur; refer to the full prescribing information for a complete list.
Pregnancy and Breastfeeding
Brentuximab vedotin can cause fetal harm. Women of childbearing potential should use effective contraception during treatment and for at least 6 months after the last dose. Men should use effective contraception during treatment and for at least 4 months after the last dose. Breastfeeding is not recommended during treatment and for an appropriate period after the last dose.
Drug Profile Summary
- Mechanism of Action: Antibody-drug conjugate targeting CD30-expressing cells, releasing MMAE to inhibit microtubule formation and induce apoptosis.
- Side Effects: Peripheral neuropathy, neutropenia, fatigue, nausea, infections. Serious side effects include PML, SJS/TEN, pulmonary toxicity.
- Contraindications: Concomitant bleomycin; hypersensitivity.
- Drug Interactions: CYP3A4 inhibitors/inducers, P-gp inhibitors/inducers.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; breastfeeding not recommended.
- Dosage: Varies depending on indication and patient factors; usually 1.8 mg/kg IV every 3 weeks.
- Monitoring Parameters: Complete blood counts (CBCs), liver function tests (LFTs), neurological assessments, signs and symptoms of infection and pulmonary toxicity.
Popular Combinations
Brentuximab vedotin is often combined with chemotherapy regimens such as AVD (doxorubicin, vinblastine, dacarbazine), CHP (cyclophosphamide, doxorubicin, prednisone), and AVE-PC (doxorubicin, vincristine, etoposide, prednisone, cyclophosphamide), depending on the type of lymphoma and treatment setting. These combinations aim to enhance efficacy through synergistic mechanisms. Brentuximab vedotin combined with nivolumab can also be an option for older adults with Hodgkin Lymphoma or patients ineligible for chemotherapy.
Precautions
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General Precautions: Evaluate patients for pre-existing peripheral neuropathy, hepatic or renal impairment, and infections before starting treatment. Monitor closely for adverse reactions, particularly PML, pulmonary toxicity, and peripheral neuropathy.
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Specific Populations: As described previously in specific sections, monitor patients that are pregnant/breastfeeding, elderly, and children.
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Lifestyle Considerations: Patients should be advised to avoid activities requiring alertness until the effects of the drug are known.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Brentuximab Vedotin?
A: The recommended dosage and schedule vary based on the indication, patient age, and other factors. Standard adult dosing is typically 1.8 mg/kg IV every 3 weeks, but adjustments are often needed. Pediatric dosing for high-risk cHL is 1.8 mg/kg IV every 3 weeks in combination with AVE-PC. Always consult the full prescribing information for detailed and up-to-date dosage guidelines for specific situations.
Q2: What are the most common side effects?
A: The most common side effects are peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, thrombocytopenia, anemia, constipation, and infections.
Q3: What are the serious side effects to watch out for?
A: Serious side effects include progressive multifocal leukoencephalopathy (PML), severe pulmonary toxicity, Stevens-Johnson syndrome, toxic epidermal necrolysis, and tumor lysis syndrome.
Q4: What are the absolute contraindications to using Brentuximab Vedotin?
A: Concomitant use with bleomycin and hypersensitivity to brentuximab vedotin or its excipients are contraindications.
Q5: How should Brentuximab Vedotin be administered?
A: It should be administered as an intravenous infusion over 30 minutes. It should not be given as an IV push or bolus injection.
Q6: Are there any specific monitoring parameters required during treatment?
A: Yes. Monitor complete blood counts (CBCs) regularly to assess for cytopenias. Monitor liver function tests (LFTs) and assess for signs and symptoms of neuropathy, infections, and pulmonary toxicity.
Q7: What are the key drug interactions?
A: Significant interactions can occur with CYP3A4 inhibitors and inducers, P-glycoprotein inhibitors and inducers and other myelosuppressive or neurotoxic drugs. Always review the patient’s current medication list for potential interactions before initiating therapy.
Q8: Can Brentuximab Vedotin be used in pregnant or breastfeeding women?
A: Brentuximab vedotin is contraindicated in pregnancy. It should not be used in breastfeeding women, or breastfeeding should be discontinued during treatment.
Q9: What is the mechanism of action of Brentuximab Vedotin?
A: It is an antibody-drug conjugate that targets the CD30 antigen on lymphoma cells. Upon binding and internalization, it releases MMAE, a cytotoxic agent that inhibits microtubule formation, leading to cell death.
Q10: What should be done if a patient develops peripheral neuropathy during treatment?
A: The dosage may need to be reduced, delayed, or discontinued depending on the severity of the neuropathy. Consult the prescribing information for specific dosage modification guidelines.
