DB08870 Brentuximab vedotin C6476H9930N1690O2030S40 149.2–151.8 kDa

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-neoplastic agent used in the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Brentuximag vedotin was approved in 2011, and in January 2012, the drug label was revised to include a boxed warning of progressive multifocal leukoencephalopathy and death following JC virus infection. INDICATION 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. ABSORPTION Brentuximab vedotin is administered only as an intravenous infusion so absorption is 100%. VOLUME OF DISTRIBUTION The steady state volume of distribution is 6-10 L. Protein binding MMAE has a plasma protein binding range of 68-82%, and highly-protein bound drugs are not likely to displace it.

METABOLISM Only a small fraction of MMAE is metabolized primarily via oxidation by CYP3A4 and CYP3A5. ROUTE OF ELIMINATION MMAE is eliminated by the feces (with 72% unchanged) and urine. HALF LIFE The terminal half-life is 4-6 days CLEARANCE MMAE is cleared by the liver but not quantitative studies have been performed. Toxicity The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy. Other toxicities include bone marrow suppression, infusion reactions, peripheral neuropathy, Stevens-Johnson syndrome, and tumor lysis syndrome.

ADCETRIS IV infusion ADCETRIS (brentuximab vedotin) is a CD30-directed antibody-drug conjugate (ADC) consisting of three components: 1) the chimeric IgG1 antibody cAC10, specific for human CD30, 2) the microtubule disrupting agent MMAE, and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10. Brentuximab vedotin has an approximate molecular weight of 153 kDa. Approximately 4 molecules of MMAE are attached to each antibody molecule. Brentuximab vedotin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesi

DOSAGE: 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. VIAL: ADCETRIS (brentuximab vedotin) for Injection is supplied as a sterile, white to off-white, preservative-free lyophilized cake or powder in single-use vials. 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. ADVERSE REACTION: Nauseated, itchy, or if you have a fever, chills, cough, or trouble breathing DRUG INTERACTION: CYP3A4 Inhibitors/Inducers HALF-LIFE: 4 to 6 days

DRUG INTERACTIONS Bleomycin Pulmonary toxicity of bleomycin may be increased. Avoid combination. Etravirine Brentuximab when used concomitantly with etravirine, may experience a decrease in serum concentrations. The levels of an active metabolite of brentuximab, monomethyl auristatin E, may decrease. It is recommended to monitor efficacy of brentuximab therapy. Natalizumab Avoid combination due to the increased risk of concurrent infection. Pimecrolimus Avoid combination due to the potential enhancement of toxic effects of immunosuppressants Tacrolimus

REFERENCE Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, Rejniak SX, Gordon KA, DeBlanc R, Toki BE, Law CL, Doronina SO, Siegall CB, Senter PD, Wahl AF: cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 Aug 15;102(4):1458-65. Epub 2003 Apr 24 http://www.ncbi.nlm.nih.gov/pubmed/25403895 http://www.ncbi.nlm.nih.gov/pubmed/25339337 http://www.ncbi.nlm.nih.gov/pubmed/25328405 http://www.ncbi.nlm.nih.gov/pubmed/25319394 http://www.ncbi.nlm.nih.gov/pubmed/25315080 http://www.ncbi.nlm.nih.gov/pubmed/25293772 http://www.ncbi.nlm.nih.gov/pubmed/25239883