Enfortumab vedotin

Identification

Summary

Enfortumab vedotin is an antibody-drug conjugate comprised of a fully human monoclonal antibody and microtubule-disrupting chemotherapeutic agent used in the treatment of advanced or metastatic urothelial cancer.

Brand Names
Padcev
Generic Name
Enfortumab vedotin
DrugBank Accession Number
DB13007
Background

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 Genetics 2 and it was first approved for use in the United States in December 2019 under the brand name PadcevTM.3 Enfortumab vedotin was later approved by the European Commission on April 13, 2022.5

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
152000.0 Da
Sequences
Not Available
Synonyms
  • Enfortumab vedotin
  • enfortumab vedotin-ejfv
External IDs
  • AGS-22M6E

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 platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.3,4 Enfortumab vedotin can also be indicated in combination with pembrolizumab in adult patients with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy under accelerated approval from the FDA.6

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofLocally advanced urothelial cancer••••••••••••••••••••••••• ••••••• •••• •••••••••• ••••• •••••••••• •••••• •• •••••••••• •••••••••••• • ••••••• •••••••••• •••••••• •••••••••••••• •••••••••••••••••••••
Used in combination to treatLocally advanced or metastatic urothelial carcinoma (uc)Regimen in combination with: Pembrolizumab (DB09037)••••••••••••••••••••••••••
Treatment ofMetastatic urothelial cancer••••••••••••••••••••••••• ••••••• •••• •••••••••• ••••• •••••••••• •••••• •• •••••••••• •••••••••••• • ••••••• •••••••••• •••••••• •••••••••••••• •••••••••••••••••••••
Contraindications & Blackbox Warnings
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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 - although 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
antibody
Humans
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.

Adverse Effects
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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.

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 Enfortumab vedotin can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Enfortumab vedotin.
AbrocitinibThe serum concentration of Enfortumab vedotin can be increased when it is combined with Abrocitinib.
AdagrasibThe serum concentration of Enfortumab vedotin can be increased when it is combined with Adagrasib.
AfatinibThe serum concentration of Enfortumab vedotin can be increased when it is combined with Afatinib.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PadcevInjection, powder, for solution20 mgIntravenousAstellas Pharma Europe Bv2022-05-11Not applicableEU flag
PadcevPowder, for solution30 mg / vialIntravenousSeagen Inc.2023-01-10Not applicableCanada flag
PadcevInjection, powder, for solution30 mgIntravenousAstellas Pharma Europe Bv2022-05-11Not applicableEU flag
PadcevPowder, for solution20 mg / vialIntravenousSeagen Inc.2021-12-20Not applicableCanada flag
Padcev EjfvInjection, powder, lyophilized, for solution30 mg/3mLIntravenousSeagen Inc.2019-12-18Not applicableUS flag

Categories

ATC Codes
L01FX13 — Enfortumab 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
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
DLE8519RWM
CAS number
1346452-25-2

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. [Article]
  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. [Article]
  3. FDA Approved Drug Products: Padcev (enfortumab vedotin-ejfv) for IV injection [Link]
  4. EMA Approved Drug Products: Padcev (enfortumab vedotin) intravenous infusion [Link]
  5. Businesswise News: European Commission Approves PADCEV™ (enfortumab vedotin) for Locally Advanced or Metastatic Urothelial Cancer [Link]
  6. FDA Approved Drug Products: Padcev (enfortumab vedotin-ejfv) for IV injection (December 2023) [Link]
  7. Pfizer Press Release: PADCEV® (enfortumab vedotin-ejfv) with KEYTRUDA® (pembrolizumab) Approved by FDA as the First and Only ADC Plus PD-1 to Treat Advanced Bladder Cancer [Link]
PubChem Substance
347911415
RxNav
2268306
Wikipedia
Enfortumab_vedotin

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
3Active Not RecruitingTreatmentBladder Cancer1somestatusstop reasonjust information to hide
3Active Not RecruitingTreatmentBladder Cancer / Ureteral Cancer / Urothelial Cancer1somestatusstop reasonjust information to hide
3Active Not RecruitingTreatmentUrinary Bladder Cancer, Muscle-invasive1somestatusstop reasonjust information to hide
3RecruitingTreatmentMuscle Invasive Bladder Cancer1somestatusstop reasonjust information to hide
3RecruitingTreatmentUrothelial Cancer1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous20 mg
Injection, powder, for solutionIntravenous30 mg
Powder, for solutionIntravenous20 mg / vial
Powder, for solutionIntravenous30 mg / vial
SolutionIntravenous20.00 mg
Injection, powder, lyophilized, for solutionIntravenous20 mg/2mL
Injection, powder, lyophilized, for solutionIntravenous30 mg/3mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Antibody
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 at October 21, 2016 02:01 / Updated at January 10, 2024 06:22