ADCETRIS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ADCETRIS (ADCETRIS).
ADCETRIS is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (brentuximab vedotin) conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE). Upon binding to CD30 on the cell surface, the ADC is internalized and trafficked to lysosomes, where MMAE is released via proteolytic cleavage. MMAE binds to tubulin and inhibits microtubule polymerization, leading to G2/M phase cell cycle arrest and apoptosis.
| Metabolism | MMAE is primarily metabolized by CYP3A4/5. Less than 5% of MMAE is metabolized by CYP2D6. The unconjugated drug is also a substrate of P-glycoprotein (P-gp). |
| Excretion | Renal (minimal, unchanged drug); biliary/fecal (monomethyl auristatin E [MMAE] is primarily eliminated via feces, with minimal renal elimination; approximately 72% of total MMAE is recovered in feces and 18% in urine over 1 week). |
| Half-life | Terminal t1/2 of ADCETRIS (brentuximab vedotin) is approximately 4–6 days; MMAE has a terminal t1/2 of approximately 3–4 days. The long half-life supports every-3-week dosing. |
| Protein binding | Brentuximab vedotin: ~68-70% bound to plasma proteins; MMAE: approximately 49–73% bound to albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | Vd for brentuximab vedotin: approximately 0.06–0.08 L/kg (central compartment); MMAE: approximately 7–10 L (total distribution), indicating extensive tissue binding. |
| Bioavailability | Intravenous only; bioavailability is 100% by IV administration. |
| Onset of Action | Clinical response (tumor reduction) typically observed within 6–8 weeks (after 2–3 cycles) in responsive patients; peak concentration is achieved at the end of the 30-minute infusion. |
| Duration of Action | Duration of clinical effect varies; in responding patients, median duration of response is approximately 13 months in relapsed Hodgkin lymphoma and 12 months in systemic anaplastic large cell lymphoma. Dosing every 3 weeks maintains therapeutic exposure. |
1.8 mg/kg administered intravenously over 30 minutes every 3 weeks.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment required for GFR >= 30 mL/min. For GFR < 30 mL/min, no specific recommendation; use with caution. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose to 1.2 mg/kg; Child-Pugh C: avoid use. |
| Pediatric use | For patients aged 2-17 years: 1.8 mg/kg (up to 180 mg) intravenously over 30 minutes every 3 weeks. |
| Geriatric use | No specific dose adjustment; monitor for increased toxicity due to age-related organ dysfunction. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ADCETRIS (ADCETRIS).
| Breastfeeding | It is not known whether brentuximab vedotin or its metabolite MMAE is present in human milk, affects the breastfed infant, or affects milk production. MMAE is excreted in rat milk at concentrations up to 28.5% of maternal plasma concentration (M/P ratio approximately 0.29 based on AUC). Because of the potential for serious adverse reactions in a breastfed infant, advise lactating women not to breastfeed during treatment with ADCETRIS and for at least 6 months after the last dose. |
| Teratogenic Risk | ADCETRIS (brentuximab vedotin) is an antibody-drug conjugate containing monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Based on its mechanism of action and animal studies, it is expected to cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of brentuximab vedotin to pregnant rats during organogenesis resulted in embryofetal lethality, decreased fetal weight, and skeletal abnormalities at maternal exposures approximately 0.9 times the human exposure at the recommended dose. There are no adequate and well-controlled studies in pregnant women. Advise pregnant women of the potential risk to a fetus. During the first trimester, there is a high risk of miscarriage and major birth defects. Second and third trimester exposure may lead to fetal growth restriction, oligohydramnios, and neonatal toxicity. Avoid use during pregnancy unless the potential benefit outweighs the risk. |
■ FDA Black Box Warning
Progressive multifocal leukoencephalopathy (PML): Cases of JC virus infection resulting in PML and death have been reported in patients receiving ADCETRIS. Symptoms include altered mental status, visual changes, motor weakness, and hemiparesis.
| Serious Effects |
["Concurrent use with bleomycin due to increased risk of pulmonary toxicity.","Known hypersensitivity to brentuximab vedotin or any of its components."]
| Precautions | ["Peripheral neuropathy: Sensory or motor neuropathy may occur, which may be progressive and require dose modification or discontinuation.","Infusion-related reactions: Including hypotension, bronchospasm, urticaria, and anaphylaxis. Premedicate with acetaminophen, antihistamines, and corticosteroids.","Hepatotoxicity: Elevations in liver enzymes and bilirubin, including fatal hepatotoxicity. Monitor liver function and adjust dose as needed.","Pulmonary toxicity: Cases of pneumonitis, interstitial lung disease, and ARDS have been reported.","Serious infections: Including opportunistic infections (e.g., PML, sepsis). Monitor for signs of infection.","Tumor lysis syndrome: May occur in patients with rapidly proliferating tumors. Monitor and manage appropriately.","Dermatologic reactions: Including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Discontinue if severe.","Gastrointestinal complications: Including pancreatitis and gastrointestinal perforation.","Hematologic toxicities: Severe neutropenia, anemia, and thrombocytopenia may occur. Monitor blood counts.","Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the last dose."] |
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| Fetal Monitoring | Monitor pregnant women exposed to ADCETRIS for fetal growth and well-being via serial ultrasounds to assess fetal growth, amniotic fluid volume, and anatomy. Perform fetal echocardiography to evaluate cardiac structure and function. Obtain baseline and periodic liver function tests and complete blood counts, as ADCETRIS can cause hepatotoxicity and myelosuppression. Monitor for peripheral neuropathy and infusion reactions. Postnatal monitoring of the infant for adverse effects related to microtubule disruption is recommended. |
| Fertility Effects | Based on animal studies, ADCETRIS may impair male and female fertility. In female dogs, brentuximab vedotin caused ovarian degeneration, depletion of ovarian follicles, and persistent anestrus. In male dogs, testicular degeneration and hypospermia were observed. The potential effects on human fertility are unknown; however, microtubule inhibitors are known to affect gametogenesis. Advise men and women of childbearing potential to use effective contraception during treatment and for at least 6 months after the last dose. Consider reproductive counseling for patients planning future fertility. |
| Food/Dietary | Grapefruit and grapefruit juice may interact; avoid concurrent use. No other significant food interactions known. |
| Clinical Pearls | ADCETRIS (brentuximab vedotin) is an antibody-drug conjugate targeting CD30. Administer with premedication for infusion reactions. Monitor for peripheral neuropathy, neutropenia, and progressive multifocal leukoencephalopathy (PML). Do not co-administer with strong CYP3A4 inducers or inhibitors without dose adjustment. Avoid live vaccines during treatment. |
| Patient Advice | Inform your doctor if you have a history of liver disease, neuropathy, or infections. · Report numbness or tingling in hands/feet, severe fatigue, or signs of infection immediately. · Do not become pregnant while taking this medication; use effective contraception. · Avoid live vaccines during treatment and for 6 months after. · Take anti-nausea medications as prescribed. |