Identification

Name
Brentuximab vedotin
Accession Number
DB08870
Description

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. Brentuximab vedotin was initially approved in 2011. In January 2012, the drug label was revised with a boxed warning of a condition known as progressive multifocal leukoencephalopathy and death due to opportunistic JC virus infection post treatment 5.

The U.S. Food and Drug Administration approved Adcetris in March 2018 to treat adult patients with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy 5.

Adcetris has also been previously approved by the FDA to treat Hodgkin's lymphoma after relapse, Hodgkin's lymphoma after stem cell transplantation when a patient has a high risk of relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after the failure of other treatment regimens, and primary cutaneous ALCL after failure of other treatment regimens 5.

Lymphoma is a malignancy that begins in the lymphatic system, which helps to combat infection and disease. Lymphoma may begin anywhere in the body and can spread to nearby lymph nodes. The two main types of lymphoma are Hodgkin lymphoma (also called Hodgkin disease) and non-Hodgkin lymphoma. Most individuals with Hodgkin's lymphoma have the classical type. In this type of lymphoma, large, abnormal lymphocytes (a type of white blood cell) are found in the lymph nodes called Reed-Sternberg cells. With early diagnosis and intervention, patients with Hodgkin lymphoma normally experience long-term remission 5.

The ECHELON-1 study results demonstrated superior efficacy of the drug combined with a chemotherapy regimen when it is compared to the previous standard of care. Importantly, removing the drug bleomycin, a highly toxic agent, was completely removed from the regimen. This demonstrates meaningful progress in treatment for patients affected by this disease 6.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb) / Fusion proteins
Protein Structure
Db08870
Protein Chemical Formula
C6476H9930N1690O2030S40
Protein Average Weight
150500.0 Da (range 149200-151800)
Sequences
Not Available
Synonyms
  • Brentuximab vedotina
  • cAC10-vcMMAE
External IDs
  • SGN 35
  • SGN-35

Pharmacology

Indication

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 5,6.

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 Label, 5.

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

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

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 Label.

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 7.

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 3.

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 Label.

Mechanism of action

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 Label.

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 Label.

TargetActionsOrganism
ATumor necrosis factor receptor superfamily member 8
binder
Humans
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 Label.

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 Label.

Protein binding

In vitro, the binding of MMAE to human plasma proteins is in the range of 68–82% 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 Label.

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Route of elimination

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 Label.

Half-life

The terminal half-life is approximately 4-6 days 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 Label. It is recommended to avoid use in patients with severe renal impairment (CrCl <30mL/min) 9.

Adverse Effects
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Toxicity

The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy 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 10.

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) 5. 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 5.

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 5.

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 5. 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 Label.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Brentuximab vedotin can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Brentuximab vedotin can be increased when combined with Abatacept.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Brentuximab vedotin.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Brentuximab vedotin.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Brentuximab vedotin.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Brentuximab vedotin.
AcetaminophenThe metabolism of Brentuximab vedotin can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Brentuximab vedotin can be decreased when combined with Acetazolamide.
AdalimumabThe metabolism of Brentuximab vedotin can be increased when combined with Adalimumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Brentuximab vedotin.
Additional Data Available
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Food Interactions
  • 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.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AdcetrisInjection, powder, for solution50 mgIntravenousTakeda Pharma A/S2012-10-25Not applicableEU flag
AdcetrisPowder, for solution50 mgIntravenousSeattle Genetics, Inc.2013-02-19Not applicableCanada flag
AdcetrisInjection, powder, lyophilized, for solution50 mg/10.5mLIntravenousSeattle Genetics, Inc.2011-08-25Not applicableUS flag
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  • Application Number
    Application Number
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    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
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Categories

ATC Codes
L01XC12 — Brentuximab vedotin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Chemical Identifiers

UNII
7XL5ISS668
CAS number
914088-09-8

References

Synthesis 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

General References
  1. 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. [PubMed:12714494]
  2. Eichenauer DA, Plutschow A, Kreissl S, Sokler M, Hellmuth JC, Meissner J, Mathas S, Topp MS, Behringer K, Klapper W, Kuhnert G, Dietlein M, Kobe C, Fuchs M, Diehl V, Engert A, Borchmann P: Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin's lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group. Lancet Oncol. 2017 Dec;18(12):1680-1687. doi: 10.1016/S1470-2045(17)30696-4. Epub 2017 Nov 10. [PubMed:29133014]
  3. Cao H, Yamamoto K, Yang LX, Weber R: Brentuximab vedotin: first-line agent for advanced Hodgkin lymphoma. Anticancer Res. 2013 Sep;33(9):3879-85. [PubMed:24023323]
  4. Horie R, Watanabe T: CD30: expression and function in health and disease. Semin Immunol. 1998 Dec;10(6):457-70. doi: 10.1006/smim.1998.0156. [PubMed:9826579]
  5. FDA expands approval of Adcetris for first-line treatment of Stage III or IV classical Hodgkin lymphoma in combination with chemotherapy [Link]
  6. Seattle Genetics Announces FDA Approval of ADCETRIS® (Brentuximab Vedotin) in Combination with Chemotherapy for Adults with Previously Untreated Stage III or IV Classical Hodgkin Lymphoma Read more: http://www.digitaljournal.com/pr/3703005#ixzz5AKAaxmbe [Link]
  7. NCCN Flash UpdatesTM: NCCN Guidelines® and NCCN Compendium® Updated [Link]
  8. EMA label [Link]
  9. Cancer Care Ontario Formulary [Link]
  10. Merck Manuals, Progressive Multifocal Leukoencephalopathy [Link]
  11. Seattle genetics Brentuximab Vedotin [Link]
  12. Brentuximab vedotin: clinical updates and practical guidance [Link]
KEGG Drug
D09587
PubChem Substance
347910376
RxNav
1147320
ChEMBL
CHEMBL1742994
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Brentuximab_vedotin
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (217 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentAnaplastic Large-Cell Lymphoma1
4CompletedTreatmentLymphoma, Hodgkins1
3Active Not RecruitingTreatmentAnaplastic Large-Cell Lymphoma / Non-Hodgkin's Lymphoma (NHL) / T-cell type lymphoma1
3Active Not RecruitingTreatmentAnn Arbor Stage IIB Hodgkin Lymphoma / Ann Arbor Stage IIIB Hodgkin Lymphoma / Ann Arbor Stage IV Hodgkin Lymphoma / Ann Arbor Stage IVA Hodgkin Lymphoma / Ann Arbor Stage IVB Hodgkin Lymphoma / Childhood Hodgkin Lymphoma / Classic Hodgkin Lymphoma1
3Active Not RecruitingTreatmentHodgkins Disease (HD)1
3Active Not RecruitingTreatmentLymphoma, Hodgkins2
3CompletedTreatmentCutaneous T-Cell Lymphoma (CTCL) / Mycosis Fungoides (MF) / Primary Cutaneous Anaplastic Large Cell Lymphoma1
3CompletedTreatmentHodgkins Disease (HD)1
3RecruitingTreatmentAnn Arbor Stage III Hodgkin Lymphoma / Ann Arbor Stage III Lymphocyte-Depleted Classic Hodgkin Lymphoma / Ann Arbor Stage III Mixed Cellularity Classic Hodgkin Lymphoma / Ann Arbor Stage III Nodular Sclerosis Classic Hodgkin Lymphoma / Ann Arbor Stage IIIA Hodgkin Lymphoma / Ann Arbor Stage IIIB Hodgkin Lymphoma / Ann Arbor Stage IV Hodgkin Lymphoma / Ann Arbor Stage IV Lymphocyte-Depleted Classic Hodgkin Lymphoma / Ann Arbor Stage IV Mixed Cellularity Classic Hodgkin Lymphoma / Ann Arbor Stage IV Nodular Sclerosis Classic Hodgkin Lymphoma / Ann Arbor Stage IVA Hodgkin Lymphoma / Ann Arbor Stage IVB Hodgkin Lymphoma / Classic Hodgkin Lymphoma / Lymphocyte-Rich Classic Hodgkin Lymphoma1
3RecruitingTreatmentClassical Hodgkin's Lymphoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous50 mg
Injection, powder, for solutionIntravenous; Parenteral50 MG
Injection, powder, lyophilized, for solutionIntravenous50 mg/10.5mL
Injection, solution, concentrateIntravenous50 mg
Powder, for solutionIntravenous50 mg
Injection, solutionIntravenous50 mg
PowderIntravenous50 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Tumor necrosis factor-activated receptor activity
Specific Function
Receptor for TNFSF8/CD30L. May play a role in the regulation of cellular growth and transformation of activated lymphoblasts. Regulates gene expression through activation of NF-kappa-B.
Gene Name
TNFRSF8
Uniprot ID
P28908
Uniprot Name
Tumor necrosis factor receptor superfamily member 8
Molecular Weight
63746.47 Da
References
  1. 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. [PubMed:12714494]
  2. Seattle genetics Brentuximab Vedotin [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Cancer Care Ontario Formulary [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Efflux transmembrane transporter activity
Specific Function
Drug efflux transporter present in a number of stem cells that acts as a regulator of cellular differentiation. Able to mediate efflux from cells of the rhodamine dye and of the therapeutic drug do...
Gene Name
ABCB5
Uniprot ID
Q2M3G0
Uniprot Name
ATP-binding cassette sub-family B member 5
Molecular Weight
138639.48 Da
References
  1. Brentuximab vedotin: clinical updates and practical guidance [Link]

Drug created on May 01, 2013 14:50 / Updated on November 23, 2020 09:08

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