Drug information of Brentuximab

Brentuximab


Brentuximab vedotin, also known as Adcetris®, is an antibody-drug conjugate that combines an anti-CD30 antibody with the drug monomethyl auristatin E (MMAE). It is an anti-neoplastic agent used in the treatment of Hodgkin's lymphoma and systemic anaplastic large cell lymphoma.

Mechanism of effect

Brentuximab vedotin is an antibody drug conjugate (ADC) directed at CD30 consisting of 3 components: 1) a CD30-specific chimeric IgG1 antibody cAC10; 2) a microtubule-disrupting agent, monomethylauristatin E (MMAE); and 3) a protease cleavable dipeptide linker (which covalently conjugates MMAE to cAC10). The conjugate binds to cells which express CD30, and forms a complex which is internalized within the cell and releases MMAE. MMAE binds to the tubules and disrupts the cellular microtubule network, inducing cell cycle arrest (G2/M phase) and apoptosis.

Pharmacodynamic

 Brentuximab vedotin causes apoptosis of tumor cells by preventing cell cycle progression of the G2 to M phase through disruption of the cytosolic microtuble network, thus preventing tumor growth and proliferation.
    Hodgkin lymphoma (HL) is characterized by malignant Reed-Sternberg cells which express CD30, a marker of large cell lymphoma 4. Until March 2018, USA National Comprehensive Cancer Network guidelines for patients with advanced HL (stage III/IV disease) recommend treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), or escalated bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) as first-line regimens.
    ABVD appears to be as effective, with fewer side effects, as escalated BEACOPP. Escalated BEACOPP leads to a greater progression-free survival but no difference in overall survival. Recent progress in technology has enabled a new shift to cancer therapy targeting specific molecules. Brentuximab vedotin, a CD30-directed antibody conjugate, selectively targets malignant HL cells.
    The effect of Brentuximab vedotin (1.8 mg/kg) on the QTc interval was studied in an open-label, single-group study in 46 patients diagnosed with CD30-expressing hematologic malignancies. Ingestion of brentuximab vedotin did not prolong the mean cardiac QTc interval >10 ms from baseline levels. Smaller increases in the mean QTc interval (<10 ms) cannot be ruled out because this study did not include a placebo arm and a positive control arm

Pharmacokinetics

Distribution: Vdss: ADC: ~6 to 10 L
Protein binding: MMAE: 68% to 82%
Metabolism: MMAE: Minimal, primarily via oxidation by CYP3A4/5
Half-life elimination: Terminal: ADC: ~4 to 6 days; MMAE: ~3 to 4 days
Time to peak: ADC: At end of infusion; MMAE: ~1 to 3 days after the end of infusion
Excretion: MMAE: Feces (~72% [of recovered MMAE], primarily unchanged); urine

Drug indications

Hodgkin's Disease , peripheral T-cell lymphoma

Primary cutaneous anaplastic large cell lymphoma, relapsed
(pcALCL)
Systemic anaplastic large cell lymphoma (sALCL), previously untreated
Systemic anaplastic large cell lymphoma, relapsed

Dosage

Hodgkin lymphoma, advanced, previously untreated: IV: 1.2 mg/kg (maximum dose: 120 mg) every 2 weeks (in combination with doxorubicin, vinblastine, and dacarbazine [AVD]; begin brentuximab within ~1 hour after completion of AVD) until a maximum of 12 doses, disease progression, or unacceptable toxicity (Connors 2018). Administer primary prophylaxis with G-CSF (filgrastim) beginning with cycle 1.
Hodgkin lymphoma, relapsed or refractory: IV: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks, continue until disease progression or unacceptable toxicities (Younes 2012)
Hodgkin lymphoma, consolidation therapy after autologous hematopoietic stem cell transplantation (HSCT): IV: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks, continue until a maximum of 16 cycles, disease progression, or unacceptable toxicity (Moskowitz 2015). Begin therapy within 4 to 6 weeks post HSCT or upon recovery from HSCT.
Mycosis fungoides (CD-30 expressing), relapsed: IV: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks, continue until a maximum of 16 cycles, disease progression, or unacceptable toxicity (Prince 2017)
Peripheral T-cell lymphoma (CD30-expressing), previously untreated: IV: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks for 6 to 8 doses (in combination with cyclophosphamide, doxorubicin, and prednisone). Administer primary prophylaxis with G-CSF (filgrastim) beginning with cycle 1.
Primary cutaneous anaplastic large cell lymphoma, relapsed (pcALCL): IV: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks, continue until a maximum of 16 cycles, disease progression, or unacceptable toxicity (Prince 2017)
Systemic anaplastic large cell lymphoma (sALCL), previously untreated: IV: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks for 6 to 8 doses (in combination with cyclophosphamide, doxorubicin, and prednisone)
Systemic anaplastic large cell lymphoma, relapsed: IV: 1.8 mg/kg (maximum dose: 180 mg) every 3 weeks, continue until disease progression or unacceptable toxicities (Pro 2012)

Drug contraindications

Concurrent use with bleomycin (due to pulmonary toxicity).
Hypersensitivity to brentuximab or any component of the formulation
 patients who have or have had progressive multifocal leukoencephalopathy

Alerts

Concerns related to adverse effects:
• Bone marrow suppression: Grade 3 or 4 neutropenia, thrombocytopenia, and anemia may occur. Neutropenia may be severe and/or prolonged (≥1 week). Neutropenic fever (sometimes fatal) also has been reported. Monitor blood counts prior to each dose; consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. May require growth factor support, dose interruption, reduction, or discontinuation. Administer primary prophylaxis with G-CSF (filgrastim) beginning with cycle 1 in patients receiving brentuximab vedotin in combination with chemotherapy for previously untreated Hodgkin lymphoma or previously untreated peripheral T-cell lymphomas (PTCL).
• Dermatologic toxicity: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (some fatal). Discontinue (and begin appropriate management) if SJS or TEN occur.
• GI toxicity: Acute pancreatitis (some fatal) has been observed. Other serious and fatal GI complications (including hemorrhage, obstruction, perforation, erosion, ulcer, enterocolitis, neutropenic colitis, and ileus) have also been reported. The risk for GI complications may be increased in patients with lymphoma with preexisting GI involvement. Prompt diagnostic evaluation and management should be performed if new or worsening GI symptoms (including severe abdominal pain) occur.
• Hepatotoxicity: Serious hepatotoxicity, including fatalities, has occurred; cases were consistent with hepatocellular injury, with elevations of transaminases and/or bilirubin. Some have occurred after the initial dose or after rechallenge. The risk for hepatotoxicity may be increased with preexisting liver disease, elevated baseline liver enzymes, and concurrent medications. Monitor liver enzymes and bilirubin. Treatment delay, dose reduction, or discontinuation may be required for new, worsening, or recurrent hepatotoxicity.
• Hyperglycemia: Hyperglycemia, including new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatalities) have been reported, including grade 3 and 4 events. The median time to hyperglycemia onset was 1 month (range: up to 10 months). Hyperglycemia occurred more frequently in patients with increased body mass or diabetes. Monitor serum glucose; if hyperglycemia is observed, administer antihyperglycemics as clinically indicated.
• Infection: Serious infection, including opportunistic infections (eg, pneumonia, bacteremia, sepsis/septic shock) have been reported (some fatal); monitor for signs or symptoms of bacterial, fungal, or viral infections.
• Infusion reactions/anaphylaxis: Infusion reactions, including anaphylaxis have been reported. Monitor during infusion. For anaphylaxis, immediately and permanently discontinue and administer appropriate medical intervention. For infusion-related reaction, interrupt infusion and administer appropriate medical intervention; premedicate for subsequent infusions (with acetaminophen, an antihistamine, and/or a corticosteroid).
• Peripheral neuropathy: Peripheral neuropathy is common and is generally cumulative. Neuropathy is usually sensory, although motor neuropathy has also been observed. Neuropathy completely resolved in over half of patients receiving brentuximab vedotin as monotherapy; almost one-quarter had partial improvement. Neuropathy did not improve in some patients. In patients receiving brentuximab as a single agent, the median time to onset of neuropathy (any grade) was 3 months (range: up to 12 months), and the median time from onset to resolution or improvement of any grade was 5 months (range: up to 45 months). In patients receiving brentuximab in combination with chemotherapy, the median time to onset of neuropathy (any grade) was 2 months (range: up to 7 months), and the median time from onset to resolution or improvement of any grade was 2 to 4 months (range: up to 45 months). Neuropathy completely resolved in approximately one-half of patients receiving brentuximab in combination with chemotherapy; ~12% to 24% had partial improvement. Monitor for symptoms of neuropathy (hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, or weakness). Dose interruption, reduction or discontinuation may be recommended for new or worsening neuropathy.
• Progressive multifocal leukoencephalopathy: [US Boxed Warning]: Cases of progressive multifocal leukoencephalopathy (PML) and death due to JC virus infection have been reported. Immunosuppression due to prior chemotherapy treatments or underlying disease may also contribute to PML development. New-onset signs/symptoms of central nervous system abnormalities (eg, changes in mood, memory, cognition, motor incoordination and/or weakness, speech and/or visual disturbances) should receive prompt evaluation with neurology consultation, brain MRI, and lumbar puncture or brain biopsy. The time to initial symptom onset varies from treatment initiation, with some cases occurring within 3 months of initial drug exposure. Withhold treatment with new-onset symptoms suggestive of PML; discontinue if diagnosis of PML is confirmed.
• Pulmonary toxicity: Noninfectious pulmonary toxicity (eg, pneumonitis, interstitial lung disease, acute respiratory distress syndrome), some fatal, has been reported in patients receiving brentuximab vedotin. Monitor for signs/symptoms of pulmonary toxicity (eg, cough, dyspnea). Withhold treatment and perform prompt diagnostic evaluation and management for new or worsening pulmonary symptoms.
• Tumor lysis syndrome: Tumor lysis syndrome (TLS) may occur; risk of TLS is higher in patients with a high tumor burden or with rapid tumor proliferation. Monitor closely.
Disease-related concerns:
• Hepatic impairment: Avoid use in patients with moderate to severe hepatic impairment (Child-Pugh classes B and C). A reduced dose is required in patients with mild impairment (Child-Pugh class A). The frequency of grade 3/4 toxicities (and deaths) was increased in patients with moderate or severe impairment (compared to patients with normal hepatic function). A component of brentuximab vedotin, the microtubule-disrupting agent monomethylauristatin E (MMAE) is excreted hepatically. MMAE exposure is increased ~2.2-fold in patients with hepatic impairment.
• Renal impairment: Avoid use in patients with severe renal impairment (CrCl <30 mL/minute). The frequency of grade 3/4 toxicities (and deaths) was increased in patients with severe impairment (compared to patients with normal renal function). A component of brentuximab vedotin, the microtubule-disrupting agent MMAE is excreted renally; MMAE exposure is increased in patients with severe impairment.

Pregnancy level

Not assigned

Based on the mechanism of action and on animal data, brentuximab vedotin may cause fetal harm if administered to a pregnant woman.

Breast feeding warning

It is not known if brentuximab vedotin is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during treatment.

Ask a Pharmacist


User's questions
    No comments yet.