Brentuximab Vedotin

Uses

Brentuximab Vedotin is a CD30-directed antibody-drug conjugate used to treat various types of lymphoma.

Seattle Genetics Announced FDA Approval of ADCETRIS® (Brentuximab Vedotin) in combination with chemotherapy for adults with previously untreated stage III or IV Classical Hodgkin Lymphoma in March 2018 .

Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates , .

Systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen .

Brentuximab Vedotin is also used to associated treatment for these conditions: B-large cell anaplastic Lymphoma (Kiel Classification) refractory, Refractory Hodgkin Lymphoma, Post-autologous hematopoietic stem cell transplantation Hodgkin lymphoma

How Brentuximab Vedotin works

Brentuximab Vedotin is composed of 3 parts: a chimeric human-murine IgG1 that selectively targets CD30, monomethyl auristatin E (MMAE), which is a microtubule-disrupting agent, and a protease-susceptible linker that links the antibody and MMAE. The IgG1 antibody enables Brentuximab Vedotin to target tumor cells expressing CD30 on their surface. Following this Brentuximab Vedotin enters the cell. Once inside, the linker is cleaved releasing MMAE which binds disrupts the microtubule network .

The antibody component of this drug is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule-disrupting particle. MMAE is covalently attached to the antibody by a linker. Data suggest that the anticancer activity of Adcertris is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the subsequent release of MMAE by proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptotis of the malignant cells .

Toxicity

The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy .

Progressive multifocal leukoencephalopathy (PML) follows infection by the JC virus (which is not related to Creutzfeldt-Jakob disease). Symptoms of this condition begin insidiously and usually worsen progressively. The symptoms vary depending on which region of the brain is infected. In about two out of three patients, mental function deteriorates rapidly, leading to dementia. Speaking and walking may become increasingly difficult. Vision may be impaired, and total blindness may occur. Rarely, headaches and seizures can occur, mainly in immunocompromised patients. The most serious sequela of this condition is death .

Common adverse effects of Adcetris may include: neutropenia, anemia, peripheral neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and fever. In one trial, neutropenia occurred in 91 percent of patients treated with Adcetris plus chemotherapy, which was associated with a 19 percent rate of febrile neutropenia (neutropenia and fever) . Preventive treatment with G-CSF, a growth factor for the bone marrow to produce white blood cells, is recommended with Adcetris plus chemotherapy for the first-line treatment of Stage III or IV cHL .

Adcetris has a boxed warning that emphasizes the risk of John Cunningham virus infection leading to progressive multifocal leukoencephalopathy, or PML, a rare but serious brain infection that may be lethal.

Serious risks of Adcetris include peripheral neuropathy; severe allergic (anaphylaxis) or infusion-site reactions; damage to the blood, lungs and liver (hematologic, pulmonary and hepato-toxicities); severe/opportunistic infections; metabolic abnormalities (tumor lysis syndrome); dermatologic reactions and gastrointestinal complications. Adcetris may cause harm to the fetus and newborn baby; women should be warned of the potential risk to the fetus and to use effective contraception, and to avoid breastfeeding while taking Adcetris .

MMAE was found to be genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting drug. Fertility studies with Brentuximab Vedotin or MMAE have not been conducted. Despite this, results of repeat-dose toxicity studies in rats suggest the potential for Brentuximab Vedotin to have a negative effect on male reproductive function and fertility. In a 4-week repeated-dose toxicity study in rats with weekly dosing at 0.5, 5 or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed . Effects in animals were seen mostly at 5 and 10 mg/kg doses of brentuximab vedotin. These dosages are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on individual body weight .

Food Interaction

• Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of monomethyl auristatin E (MMAE), the antitumor component of brentuximab vedotin.
• Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of monomethyl auristatin E (MMAE), the antitumor component of brentuximab vedotin.

Volume of Distribution

MMAE is unlikely to displace or to be displaced by highly protein-bound drugs. In vitro studies show that MMAE is a substrate of P-gp and was not a potent inhibitor of P-gp .

Elimination Route

Steady-state of the ADC is achieved within 21 days with every 3-week dosing of Adcetris. Minimal to no accumulation of ADC is observed with multiple doses at the every 3-week schedule. The time to maximum concentration for MMAE ranges from approximately 1 to 3 days. Similar to the ADC, steady-state of MMAE is achieved within 21 days with every 3-week dosing of Adcetris. MMAE exposures decrease with continued administration of Adcetris with about 50% to 80% of the exposure of the first dose being observed at future doses. The AUC of MMAE was measured to be approximately 2.2-fold higher in patients with hepatic impairment in comparison with patients with normal hepatic function .

Half Life

The terminal half-life is approximately 4-6 days .

Clearance

The liver is the primary route of clearance for MMAE. The pharmacokinetics and safety of Brentuximab Vedotin and MMAE were examined after the administration of 1.2 mg/kg of Adcetris to patients with mild, moderate, and severe hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ≥Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function . It is recommended to avoid use in patients with severe renal impairment (CrCl 9.

Elimination Route

This drug appears follow metabolite kinetics, with the elimination of appearing to be limited by its rate of release from the antibody-drug conjugate (ADC). An excretion study was done in patients receiving a dose of 1.8 mg/kg of Adcetris. About 24% of the total MMAE ingested as part of the ADC during an ADCETRIS infusion was recovered in both urine and feces over a 7-day time frame. Of the recovered MMAE, approximately 72% was found in the feces and the majority of the excreted MMAE was excreted as unchanged drug .

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