Identification

Summary

Tisotumab vedotin is a tissue factor-directed antibody drug conjugate that is used to treat adults with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Brand Names
Tivdak
Generic Name
Tisotumab vedotin
DrugBank Accession Number
DB16732
Background

Tisotumab vedotin is a tissue factor-directed antibody-drug conjugate (ADC) comprised of an anti-tissue factor (TF) human IgG1-kappa antibody conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent, via a protease-cleavable valine-citrulline linker. Each monoclonal antibody molecule carries an average of four MMAE molecules. Tisotumab vedotin is the first TF-directed ADC 1 that works by binding to TFs expressed on solid tumours. TF is a primary initiator of the extrinsic blood coagulation cascade 3 and plays a key role in tumor-associated angiogenesis, progression, and metastasis for tumor survival. TF is a novel target for cancers, as it is often overexpressed on solid tumours, including cervical cancer, and it is associated with poor clinical outcomes. Tisotumab vedotin targets TF-expressing cells to deliver MMAE to induce direct cytotoxicity and bystander killing of neighboring cells.1

On September 20, 2021, the FDA granted accelerated approval to tisotumab vedotin-tftv for the treatment of recurrent or metastatic cervical cancer in adults in whom the disease progressed during or after chemotherapy. This is the first and only approved antibody-drug conjugate for this therapeutic indication. The approval was based on tumour response and the durability of the response as demonstrated in InnovaTV 204 (NCT03438396): in this trial, the objective response rate was 24% and the median response duration was 8.3 months.4 Tisotumab vedotin-tftv is marketed under the trade name Tivdak as an intravenous injection. Tisotumab vedotin is currently under investigation as a treatment for other solid tumors, including ovarian, lung, colorectal, pancreatic, and head and neck cancers. It is also being investigated for the combination use with other chemotherapeutic agents for recurrent or metastatic cervical cancer.2

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
153000.0 Da (approximate)
Sequences
Not Available
Synonyms
  • HuMax-TF-ADC
  • Tisotumab vedotin
  • tisotumab vedotin-tftv
External IDs
  • GCT1015-04
  • IGG1-1015-011-1006
  • TF-011-MMAE
  • WHO 10148

Pharmacology

Indication

Tisotumab vedotin is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.3

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Tisotumab vedotin is an anticancer antibody-drug conjugate that is made up of an antibody and monomethyl auristatin E (MMAE), a cytotoxic component of the drug. It works by binding to tissue factors expressed on cervical tumours and releasing MMAE upon cell entry to mediate its cytotoxic activity. Apart from directly killing tumour cells, tisotumab vedotin may exert a bystander effect by killing neighbouring cells 1 and promote immunogenic cell death pathways, including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.3

Mechanism of action

Tisotumab vedotin is a tissue factor (TF)-directed antibody-drug conjugate (ADC) anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavable vc (valine-citrulline) linker. It may exhibit multiple mechanisms of action; however, it primarily works by inducing cytotoxic effects on TF-expressing tumours. Tisotumab vedotin binds to TFs expressed on cervical tumours, which leads to the internalization of the antibody-drug conjugate-TF complex. Once internalized, MMAE from the drug-target complex is released via proteolytic cleavage. MMAE is a microtubule-disrupting agent that disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death.3

Tisotumab vedotin may also promote bystander killing of neighbouring cells. According to in vitro studies, tisotumab vedotin induces immunogenic cell death and promotes tumour cell death through Fcγ receptor-mediated effector functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Tisotumab vedotin may inhibit TF-activated factor VII (FVIIa)–dependent intracellular signalling, with negligent effects on procoagulant activity.1

TargetActionsOrganism
ATissue factor
antibody
Humans
Absorption

Following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg, the peak concentrations reached near the end of the infusion, while unconjugated MMAE concentrations peaked approximately two to three days after tisotumab vedotin-tftv dosing. The mean (± SD) Cmax of tisotumab vedotin-tftv was 40.8 (8.12) μg/mL and the mean (± SD) AUC was 57.5 (13.4) day x μg/mL. The mean (± SD) Cmax of unconjugated MMAE was 5.91 (4.2) ng/mL and the mean (± SD) AUC was 50 (35.8) day x ng/mL. The Cmax of tisotumab vedotin-tftv increased proportionally and there was no drug accumulation. Steady-state concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after one treatment cycle.3

Volume of distribution

The tisotumab vedotin-tftv steady-state volume of distribution is 7.83 (%CV: 19.1) L.3

Protein binding

Plasma protein binding of MMAE ranged from 68% to 82% in vitro.3

Metabolism

Tisotumab vedotin-tftv most likely undergoes catabolism to form small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Via proteolytic cleavage, tisotumab vedotin-tftv releases unconjugated MMAE, which is primarily metabolized by CYP3A4 in vitro.3

Route of elimination

The excretion of tisotumab vedotin-tftv is not fully characterized. Following a single-dose of another antibody-drug conjugate that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin-tftv administration.3

Half-life

The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, respectively.3

Clearance

The linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv.3

Adverse Effects
Adverseeffects
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Toxicity

There is no information on the LD50 values and overdose profile of tisotumab vedotin.

Tisotumab vedotin is associated with a risk for ocular toxicity. In clinical trials, ocular adverse reactions occurred in 60% of patients with cervical cancer. The most common reactions were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). More severe reactions included ulcerative keratitis, ulcerative keratitis with perforation requiring corneal transplantation, and symblepharon in patients with other tumor types.3

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 Tisotumab vedotin can be increased when it is combined with Abametapir.
AbirateroneThe metabolism of Tisotumab vedotin can be decreased when combined with Abiraterone.
AmiodaroneThe metabolism of Tisotumab vedotin can be decreased when combined with Amiodarone.
AmprenavirThe metabolism of Tisotumab vedotin can be decreased when combined with Amprenavir.
ApalutamideThe metabolism of Tisotumab vedotin can be increased when combined with Apalutamide.
AprepitantThe metabolism of Tisotumab vedotin can be decreased when combined with Aprepitant.
AtazanavirThe metabolism of Tisotumab vedotin can be decreased when combined with Atazanavir.
BerotralstatThe metabolism of Tisotumab vedotin can be decreased when combined with Berotralstat.
BoceprevirThe metabolism of Tisotumab vedotin can be decreased when combined with Boceprevir.
CarbamazepineThe metabolism of Tisotumab vedotin can be increased when combined with Carbamazepine.
Interactions
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Food Interactions
No interactions found.

Products

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International/Other Brands
Tivdak (Seagen Inc. and Genmab A/S)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TivdakInjection, powder, for solution40 mg/4mLIntravenousSeagen Inc.2021-09-20Not applicableUS flag

Categories

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
Not Available

Chemical Identifiers

UNII
T41737F88A
CAS number
1418731-10-8

References

General References
  1. Hong DS, Concin N, Vergote I, de Bono JS, Slomovitz BM, Drew Y, Arkenau HT, Machiels JP, Spicer JF, Jones R, Forster MD, Cornez N, Gennigens C, Johnson ML, Thistlethwaite FC, Rangwala RA, Ghatta S, Windfeld K, Harris JR, Lassen UN, Coleman RL: Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer. Clin Cancer Res. 2020 Mar 15;26(6):1220-1228. doi: 10.1158/1078-0432.CCR-19-2962. Epub 2019 Dec 3. [Article]
  2. Coleman RL, Lorusso D, Gennigens C, Gonzalez-Martin A, Randall L, Cibula D, Lund B, Woelber L, Pignata S, Forget F, Redondo A, Vindelov SD, Chen M, Harris JR, Smith M, Nicacio LV, Teng MSL, Laenen A, Rangwala R, Manso L, Mirza M, Monk BJ, Vergote I: Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021 May;22(5):609-619. doi: 10.1016/S1470-2045(21)00056-5. Epub 2021 Apr 9. [Article]
  3. FDA Approved Drug Products: TIVDAK (tisotumab vedotin-tftv) for injection, for intravenous use [Link]
  4. Drugs.com News: FDA Grants Accelerated Approval for Tivdak [Link]
RxNav
2571093
Wikipedia
Tisotumab_vedotin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentCervical Cancer1
2Active Not RecruitingTreatmentCervical Cancer1
2Active Not RecruitingTreatmentFallopian Tubes Cancer / Malignant Peritoneal Neoplasm / Ovarian Cancer1
2CompletedTreatmentBladder Cancer, Cancer / Cervix Cancer / Endometrial Cancer / Non-Small Cell Lung Carcinoma (NSCLC) / Oesophagus Cancer / Ovarian Cancer / Prostate Cancer / Squamous Cell Carcinoma of the Head and Neck (SCCHN)1
2RecruitingTreatmentExocrine Pancreatic Cancer / Neoplasms, Colorectal / Non-Small Cell Lung Carcinoma (NSCLC) / Squamous Cell Carcinoma of the Head and Neck (SCCHN)1
1, 2Active Not RecruitingTreatmentCervical Cancer1
1, 2Active Not RecruitingTreatmentSolid Tumors1
1, 2CompletedTreatmentBladder Cancer, Cancer / Castration Resistant Prostate Cancer / Cervix Cancer / Endometrial Cancer / Non-Small Cell Lung Carcinoma (NSCLC) / Oesophagus Cancer / Ovarian Cancer1
1, 2CompletedTreatmentBladder Cancer, Cancer / Castration Resistant Prostate Cancer / Cervix Cancer / Endometrial Cancer / Non-Small Cell Lung Carcinoma (NSCLC) / Oesophagus Cancer / Ovarian Cancer / Squamous Cell Carcinoma of the Head and Neck (SCCHN)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous40 mg/4mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Protease binding
Specific Function
Initiates blood coagulation by forming a complex with circulating factor VII or VIIa. The [TF:VIIa] complex activates factors IX or X by specific limited protolysis. TF plays a role in normal hemos...
Gene Name
F3
Uniprot ID
P13726
Uniprot Name
Tissue factor
Molecular Weight
33067.3 Da
References
  1. Hong DS, Concin N, Vergote I, de Bono JS, Slomovitz BM, Drew Y, Arkenau HT, Machiels JP, Spicer JF, Jones R, Forster MD, Cornez N, Gennigens C, Johnson ML, Thistlethwaite FC, Rangwala RA, Ghatta S, Windfeld K, Harris JR, Lassen UN, Coleman RL: Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer. Clin Cancer Res. 2020 Mar 15;26(6):1220-1228. doi: 10.1158/1078-0432.CCR-19-2962. Epub 2019 Dec 3. [Article]
  2. FDA Approved Drug Products: TIVDAK (tisotumab vedotin-tftv) for injection, for intravenous use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
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: TIVDAK (tisotumab vedotin-tftv) for injection, for intravenous use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
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: TIVDAK (tisotumab vedotin-tftv) for injection, for intravenous use [Link]

Drug created at September 21, 2021 20:14 / Updated at November 08, 2021 03:40