Identification

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Name
Enfortumab vedotin
Accession Number
DB13007
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Enfortumab vedotin is an antibody-drug conjugate used in the treatment of patients with advanced, treatment-resistant urothelial cancers.3 It is comprised of a fully human monoclonal antibody targeted against Nectin-4 and a microtubule-disrupting chemotherapeutic agent, monomethyl auristatin E (MMAE), joined by a protease-cleavable link.3 It is similar to brentuximab vedotin, another antibody conjugated with MMAE that targets CD-30 instead of Nectin-4.

The clinical development of enfortumab vedotin was the result of a collaboration between Astellas Pharma and Seattle Genetics2 and it was first approved for use in the United States in December 2019 under the brand name PadcevTM.3

Protein chemical formula
Not Available
Protein average weight
152000.0 Da
Sequences
Not Available
Synonyms
  • enfortumab vedotin-ejfv
External IDs
AGS-22M6E
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Padcev EjfvInjection, powder, lyophilized, for solution30 mg/3.3mLIntravenousSeattle Genetics, Inc.2019-12-18Not applicableUs
Padcev EjfvInjection, powder, lyophilized, for solution20 mg/2.3mLIntravenousSeattle Genetics, Inc.2019-12-18Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    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

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
DLE8519RWM
CAS number
1346452-25-2

Pharmacology

Indication

Enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.3

Associated Conditions
Pharmacodynamics

Enfortumab vedotin is an anti-cancer agent that destroys tumor cells by inhibiting their ability to replicate.3 Patients with moderate to severe hepatic impairment should not use enfortumab vedotin - though it has not been studied in this population, other MMAE-containing antibody-drug conjugates have demonstrated increased rates of adverse effects in patients with moderate-severe hepatic impairment.3 Enfortumab vedotin may also cause significant hyperglycemia leading, in some cases, to diabetic ketoacidosis, and should not be administered to patients with a blood glucose level >250 mg/dl.3

Mechanism of action

Enfortumab vedotin is an antibody-drug conjugate comprised of multiple components.3 It contains a fully human monoclonal antibody directed against Nectin-4, an extracellular adhesion protein which is highly expressed in urothelial cancers,1 attached to a chemotherapeutic microtubule-disrupting agent, monomethyl auristatin E (MMAE). These two components are joined via a protease-cleavable linker. Enfortumab vedotin binds to cells expressing Nectin-4 and the resulting enfortumab-Nectin-4 complex is internalized into the cell. Once inside the cell, MMAE is released from enfortumab vedotin via proteolytic cleavage and goes on to disrupt the microtubule network within the cell, arresting the cell cycle and ultimately inducing apoptosis.3

TargetActionsOrganism
UNectin-4
binder
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

Following the first treatment cycle, Cmax and AUC0-28d for enfortumab vedotin were 28 µg/mL and 111 µg.d/mL, respectively. The Cmax and AUC0-28d of unconjugated MMAE following the same cycle were 4.8 ng/mL and 69 ng.d/mL, respectively.3 The Tmax of MMAE is 1-3 days following the end of the infusion.1

Volume of distribution

The estimated steady-state volume of distribution is 11 L.3

Protein binding

MMAE was found to be 68-82% protein-bound in vitro.3 The specific proteins to which MMAE is bound have not been elucidated.

Metabolism

The catabolism of enfortumab vedotin has not been studied in humans.3 Given its structure, it is expected to be catabolized to smaller peptides, amino acids, unconjugated MMAE, and MMAE metabolites. MMAE is released from enfortumab vedotin via proteolytic cleavage by intracellular proteases and is metabolized primarily by CYP3A4 in vitro.3

Route of elimination

Excretion kinetics have not been fully characterized, but may be extrapolated from data available from another MMAE-containing antibody-drug conjugate - kinetic studies of this drug demonstrated that 17% of the total MMAE administered was recovered in feces, and 6% was recovered in urine, primarily as unchanged drug, over a 1-week period.3

Half life

The elimination half-lives of enfortumab vedotin and MMAE are 3.4 days and 2.4 days, respectively.3

Clearance

The mean clearance of enfortumab vedotin and free MMAE was 0.10 L/h and 2.7 L/h, respectively.3 The clearance of MMAE appears to be limited by its rate of release from enfortumab vedotin.

Toxicity

Toxicity information regarding enfortumab vedotin is not readily available. Patients experiencing an overdose are likely at an increased risk of severe adverse effects such as significant nausea, vomiting, neuropathy, or rash.3 Symptomatic and supportive measures are recommended.

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
AbemaciclibThe serum concentration of Enfortumab vedotin can be increased when it is combined with Abemaciclib.
AcebutololThe serum concentration of Enfortumab vedotin can be increased when it is combined with Acebutolol.
AcetaminophenThe serum concentration of Enfortumab vedotin can be increased when it is combined with Acetaminophen.
Acetylsalicylic acidThe serum concentration of Enfortumab vedotin can be increased when it is combined with Acetylsalicylic acid.
AfatinibThe serum concentration of Enfortumab vedotin can be increased when it is combined with Afatinib.
AlbendazoleThe serum concentration of Enfortumab vedotin can be increased when it is combined with Albendazole.
AldosteroneThe serum concentration of Enfortumab vedotin can be increased when it is combined with Aldosterone.
AlectinibThe serum concentration of Enfortumab vedotin can be increased when it is combined with Alectinib.
AlfentanilThe serum concentration of Enfortumab vedotin can be increased when it is combined with Alfentanil.
AlitretinoinThe serum concentration of Enfortumab vedotin can be increased when it is combined with Alitretinoin.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
Not Available

References

General References
  1. Hanna KS: Clinical Overview of Enfortumab Vedotin in the Management of Locally Advanced or Metastatic Urothelial Carcinoma. Drugs. 2019 Dec 10. pii: 10.1007/s40265-019-01241-7. doi: 10.1007/s40265-019-01241-7. [PubMed:31823332]
  2. McGregor BA, Sonpavde G: Enfortumab Vedotin, a fully human monoclonal antibody against Nectin 4 conjugated to monomethyl auristatin E for metastatic urothelial Carcinoma. Expert Opin Investig Drugs. 2019 Oct;28(10):821-826. doi: 10.1080/13543784.2019.1667332. Epub 2019 Sep 17. [PubMed:31526130]
  3. FDA Approved Drug Products: Padcev (enfortumab vedotin-ejfv) for IV injection [Link]
External Links
PubChem Substance
347911415
Wikipedia
Enfortumab_vedotin
FDA label
Download (228 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentMetastatic Urothelial Cancer and Other Malignant Solid Tumors1
1CompletedTreatmentMetastatic Urothelial Cancer1
1CompletedTreatmentNeoplasms / Oncology, Medical / Tumors1
1RecruitingTreatmentRenal Pelvis Neoplasms / Transitional Cell Carcinoma / Ureteral Neoplasms / Urethral Neoplasms / Urinary Bladder Neoplasms / Urologic Neoplasms / Urothelial Cancer1
1, 2RecruitingTreatmentTransitional Cell Carcinoma1
2Not Yet RecruitingTreatmentLocally Advanced or Metastatic Malignant Solid Tumors1
2RecruitingTreatmentRenal Pelvis Neoplasms / Transitional Cell Carcinoma / Ureteral Neoplasms / Urethral Neoplasms / Urinary Bladder Neoplasms / Urologic Neoplasms / Urothelial Cancer1
3Not Yet RecruitingTreatmentUrothelial Cancer1
3RecruitingTreatmentBladder Cancers / Ureteral Cancer / Urothelial Cancer1
Not AvailableApproved for MarketingNot AvailableLocally Advanced or Metastatic Urothelial Carcinoma (UC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous20 mg/2.3mL
Injection, powder, lyophilized, for solutionIntravenous30 mg/3.3mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Seems to be involved in cell adhesion through trans-homophilic and -heterophilic interactions, the latter including specifically interactions with NECTIN1. Does not act as receptor for alpha-herpesvirus entry into cells.
Specific Function
Cell adhesion molecule binding
Gene Name
NECTIN4
Uniprot ID
Q96NY8
Uniprot Name
Nectin-4
Molecular Weight
55453.875 Da
References
  1. FDA Approved Drug Products: Padcev (enfortumab vedotin-ejfv) for IV injection [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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. FDA Approved Drug Products: Padcev (enfortumab vedotin-ejfv) for IV injection [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Padcev (enfortumab vedotin-ejfv) for IV injection [Link]

Drug created on October 20, 2016 20:01 / Updated on December 24, 2019 04:10