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| Primary information |
|---|
| ID | 10632 |
| Therapeutic ID | Th1130 |
| Protein Name | Brentuximab vedotin |
| Sequence | >Th1130_Brentuximab_vedotin
QIQLQQSGPEVVKPGASVKISCKASGYTFTDYYITWVK
|
| Molecular Weight | 149200-151800 |
| Chemical Formula | C6476H9930N1690O2030S40 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | Terminal half-life is 4-6 days |
| Description | Brentuximag vedotin or Adcetris is an antibody-drug conjugate that combines an anti-CD30 antibody and the drug monomethyl auristatin E (MMAE). It is an anti-cancer drug used to treat Hodgkin lymphoma and systemic anaplastic large cell lymphoma. It was approved in 2011 but in January 2012, the drug label was revised to include a boxed warning of progressive multifocal leukoencephalopathy and death following JC virus infection. |
| Indication/Disease | Used in the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma. |
| Pharmacodynamics | Brentuximag vedotin causes apoptosis of tumor cells by preventing cell cycle progression of the G2 to M phase through disruption of the cytosolic mictrotuble network. |
| Mechanism of Action | Brentuximab vedotin is composed of 3 parts: a chimeric human-murine IgG1 that targets CD30, monomethyl auristatin E (MMAE),which is a microtubule disrupting agent, and a protease-susceptible linker that covalently links the antibody and MMAE. The IgG1 antibody enables brentuximab vedotin to target tumor cells expressing CD30 on their cell surface then brentuximab vedotin gets internalized into the cell. Once inside, the linker is cleaved releasing MMAE which binds disrupts the microtuble network. |
| Toxicity | The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy [FDA label]. 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 [L1743]. 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) [L1737]. 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 [L1737]. 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 [L1737]. 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 [L1737]. 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 [FDA label]. |
| Metabolism | Data in both animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes [FDA LABEL]. |
| Absorption | 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 [FDA label]. |
| 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 [FDA label]. |
| 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 [FDA label]. It is recommended to avoid use in patients with severe renal impairment (CrCl <30mL/min) [L1742]. |
| Categories | NA |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Tumor necrosis factor receptor superfamily member 8 |
| Brand Name | Adcetris |
| Company | Seattle Genetics |
| Brand Description | Seattle Genetics |
| Prescribed For | Hodgkin lymphoma (HL) 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. |
| Chemical Name | NA |
| Formulation | Following reconstitution with 10.5 mL Sterile Water for Injection, USP, a solution containing 5 mg/mL brentuximab vedotin is produced. The reconstituted product contains 70 mg/mL trehalose dihydrate, 5.6 mg/mL sodium citrate dihydrate, 0.21 mg/mL citric acid monohydrate, and 0.20 mg/mL polysorbate 80 and water for injection. The pH is approximately 6.6. |
| Physical Appearance | ADCETRIS (brentuximab vedotin) for Injection is supplied as a sterile, white to off-white, preservative-free lyophilized cake or powder in single-use vials. |
| Route of Administration | Intravenous infusion |
| Recommended Dosage | Normal renal and hepatic function (1.8 mg/kg up to 180 mg), Mild (creatinine clearance > 50-80 mL/min) or moderate (creatinine clearance 30-50 mL/min) (1.8 mg/kg up to 180 mg), Severe (creatinine clearance less than 30 mL/min) (Avoid use), Mild (Child-Pugh A) (1.2 mg/kg up to 120 mg), Moderate (Child-Pugh B) or severe (Child-Pugh C) (Avoid use). |
| Contraindication | concomitant bleomycin due to pulmonary toxicity |
| Side Effects | Peripheral neuropathy, Anaphylaxis and Infusion Reactions, Hematologic Toxicities, Serious Infections and Opportunistic Infections, Tumor Lysis Syndrome, Increased Toxicity in the Presence of Severe Renal Impairment, Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment, Hepatotoxicity, Progressive Multifocal Leukoencephalopathy, Serious Dermatologic Reactions, Embryo-Fetal Toxicity |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |