Tivozanib

Identification

Summary

Tivozanib is a kinase inhibitor to treat adult patients with renal cell carcinoma (RCC) who have failed prior systemic therapies or experienced relapsed disease.

Brand Names
Fotivda
Generic Name
Tivozanib
DrugBank Accession Number
DB11800
Background

Renal cell carcinoma (RCC) is responsible for 3% of cancer cases2 and is one of the 10 most common cancers in adults. The average age of diagnosis is between age 65 to 74.10 Tivozanib, also known as FOTIVDA, is a kinase inhibitor developed to treat adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) after prior failed systemic therapies. It was approved on March 10, 2021 by the FDA. Marketed by Aveo Oncology, tivozanib is a promising therapy for individuals with RCC who have not been treated successfully with other therapies.9

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 454.863
Monoisotopic: 454.104397445
Chemical Formula
C22H19ClN4O5
Synonyms
  • Tivozanib
External IDs
  • AV 951
  • AV-951
  • AV951
  • KIL-8951
  • KRN 951
  • KRN-951

Pharmacology

Indication

Tivozanib is approved in the USA for the treatment of relapsed or refractory renal cell carcinoma in adult patients who have undergone two or more systemic therapies.9 In the UK and other countries, is indicated as first line therapy of adults with advanced renal cell carcinoma (RCC) and VEGFR and mTOR pathway inhibitor-naïve patients after disease progression following one previous treatment with cytokine therapy for advanced disease.8

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Tivozanib inhibits growth factor receptors, treating renal cell carcinoma. In mice and rats, tivozanib inhibits tumour angiogenesis, tumour growth, and vascular permeability.9 Tivozanib was shown to frequently cause hypertension in clinical trials; hypertension must be managed before initiating therapy. Cardiac QT segment prolongation was reported in a tivozanib cardiac safety study, however the reactions were not considered clinically serious.8 In clinical studies, levels of serum soluble VEGFR2 (sVEGFR2) decreased with time and this effect increased with tivozanib exposure, and sVEGFR2 may serve as a pharmacodynamic marker of VEGFR inhibition.13

Mechanism of action

The VHL mutation-HIF upregulation-VEGF transcription is the main pathway implicated in the growth of renal cell carcinoma. Vascular endothelial growth factor receptors (VEGFR receptors) are important targets for tyrosine kinase inhibitors, which halt the growth of tumours.7 Tivozanib is a tyrosine kinase inhibitor that exerts its actions by inhibiting the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2 and VEGFR-3 and inhibits other kinases such as c-kit and platelet derived growth factor beta (PDGFR β). The above actions inhibit tumour growth and progression, treating renal cell carcinoma.7,9

TargetActionsOrganism
AVascular endothelial growth factor receptor 1
inhibitor
Humans
AVascular endothelial growth factor receptor 2
inhibitor
Humans
AVascular endothelial growth factor receptor 3
inhibitor
Humans
AMast/stem cell growth factor receptor Kit
inhibitor
Humans
APlatelet-derived growth factor receptor beta
inhibitor
Humans
UReceptor-type tyrosine-protein kinase FLT3
inhibitor
Humans
UPlatelet-derived growth factor receptor alpha
inhibitor
Humans
UProtein-tyrosine kinase 6Not AvailableHumans
UAngiopoietin-1 receptorNot AvailableHumans
UFibroblast growth factor receptor 1
inhibitor
Humans
UHepatocyte growth factor receptor
inhibitor
Humans
Absorption

The median Tmax of tivozanib is 10 hours, however, can range from 3 to 24 hours.9 A pharmacokinetic study in 8 healthy subjects revealed a Cmax and AUC for radiolabeled tivozanib of 12.1 ± 5.67 ng/mL and 1084 ± 417.0 ng·h/mL, respectively.3 Steady-state tivozanib concentrations are achieved at concentrations 6-7 times higher the normal dose.13

Volume of distribution

Tivozanib has an apparent volume of distribution (V/F) of 123 L.9

Protein binding

In vitro, the protein binding of tivozanib is mainly bound to albumin at a rate of ≥ 99%.9

Metabolism

Tivozanib is primarily metabolized by CYP3A4.4,8 After oral ingestion of a radiolabeled 1.34 mg dose of tivozanib in healthy volunteers, unchanged tivozanib accounted for 90% of the radioactive drug detected in serum.9

Route of elimination

Tivozanib is primarily excreted in the feces. After oral ingestion of a radiolabeled 1.34 mg dose of tivozanib in healthy volunteers, 79% of the administered dose was found in the feces (with 26% unchanged) and 12% was found in the urine solely as metabolites.3,9

Half-life

The half-life of tivozanib is about 111 hours according to prescribing information.9 Information from clinical studies reveals a half-life of 4-5 days.3,13

Clearance

The apparent clearance (CL/F) of tivozanib is approximately 0.75 L/h.9

Adverse Effects
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Toxicity

LD50 information for tivozanib is not readily available in the literature, however the European Medicines Agency (EMA) assessment report indicates the oral maximum tolerated dose (MTD) in mice was 524 mg/kg; doses ≥ 750 mg/kg led to severe and lethal effects. In rats, the oral MTD was to 276 mg/kg; at doses ≥ 369 mg/kg, severe effects and death occurred.12

In tivozanib monotherapy studies, two patients received overdoses of tivozanib. One volunteer with a prior history of hypertension experienced aggravated uncontrolled hypertension that resulted in death after taking 3 doses of 1340 microgram tivozanib in one day (total of 4020 micrograms). A second patient patient ingested two doses of 1340 microgram tivozanib in one day (total of 2680 micrograms), and experienced no adverse effects. Carefully control blood pressure before starting tivozanib; regularly monitor blood pressure during treatment. In the case of a confirmed or suspected overdose, discontinue tivozanib, monitor the patient closely, and provide supportive treatment as necessary. No antidote exists for an overdose with tivozanib.8

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
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Tivozanib.
AbemaciclibTivozanib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
AcetaminophenThe metabolism of Tivozanib can be increased when combined with Acetaminophen.
AfatinibTivozanib may decrease the excretion rate of Afatinib which could result in a higher serum level.
AllopurinolTivozanib may decrease the excretion rate of Allopurinol which could result in a higher serum level.
AlpelisibThe metabolism of Tivozanib can be increased when combined with Alpelisib.
AmbrisentanThe serum concentration of Tivozanib can be increased when it is combined with Ambrisentan.
AminoglutethimideThe metabolism of Tivozanib can be increased when combined with Aminoglutethimide.
AmiodaroneThe serum concentration of Tivozanib can be increased when it is combined with Amiodarone.
AmobarbitalThe metabolism of Tivozanib can be increased when combined with Amobarbital.
Interactions
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Food Interactions
  • Take with or without food.

Products

Products
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Product Ingredients
IngredientUNIICASInChI Key
Tivozanib hydrochloride8A9H4VK35Z682745-41-1RQXMKRRBJITKRN-UHFFFAOYSA-N
International/Other Brands
Fotivda (AVEO Oncology)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FotivdaCapsule1340 ?gOralEusa Pharma (Netherlands) Bv2020-12-16Not applicableEU flag
FotivdaCapsule0.89 mg/1OralAveo Pharmaceuticals, Inc.2021-03-10Not applicableUS flag
FotivdaCapsule890 ?gOralEusa Pharma (Netherlands) Bv2020-12-16Not applicableEU flag
FotivdaCapsule1.34 mg/1OralAveo Pharmaceuticals, Inc.2021-03-10Not applicableUS flag

Categories

ATC Codes
L01XE34 — Tivozanib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Ethers
Direct Parent
Diarylethers
Alternative Parents
Quinolines and derivatives / N-phenylureas / Anisoles / Phenoxy compounds / Alkyl aryl ethers / Chlorobenzenes / Pyridines and derivatives / Imidolactams / Aryl chlorides / Isoxazoles
show 10 more
Substituents
Alkyl aryl ether / Anisole / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Benzenoid / Carbonic acid derivative / Carbonyl group
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
172030934T
CAS number
475108-18-0
InChI Key
SPMVMDHWKHCIDT-UHFFFAOYSA-N
InChI
InChI=1S/C22H19ClN4O5/c1-12-8-21(27-32-12)26-22(28)25-16-5-4-13(9-15(16)23)31-18-6-7-24-17-11-20(30-3)19(29-2)10-14(17)18/h4-11H,1-3H3,(H2,25,26,27,28)
IUPAC Name
1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methyl-1,2-oxazol-3-yl)urea
SMILES
COC1=C(OC)C=C2C(OC3=CC(Cl)=C(NC(=O)NC4=NOC(C)=C4)C=C3)=CC=NC2=C1

References

Synthesis Reference

Liu, M. X., Hu, L. X., Wang, X. W., & Zhu, H. D. (2011). Synthesis of Anti-Cancer Targeted Therapies Drug Tivozanib. Advanced Materials Research, 396–398, 1490–1492. https://doi.org/10.4028/www.scientific.net/amr.396-398.1490

General References
  1. Cairns P: Renal cell carcinoma. Cancer Biomark. 2010;9(1-6):461-73. doi: 10.3233/CBM-2011-0176. [Article]
  2. Pallagani L, Choudhary GR, Himanshu P, Madduri VKS, Singh M, Gupta P, Shrivastava N, Baid G, Meenakshi R, Aasma N, Pareek P, Sanjeev M: Epidemiology and Clinicopathological Profile of Renal Cell Carcinoma: A Review from Tertiary Care Referral Centre. J Kidney Cancer VHL. 2021 Jan 20;8(1):1-6. doi: 10.15586/jkcvhl.2021.154. eCollection 2021. [Article]
  3. Cotreau MM, Hale CL, Jacobson L, Oelke CS, Strahs AL, Kochan RG, Sanga M, Slichenmyer W, Vargo DL: Absorption, Metabolism, and Excretion of [(14) C]-Tivozanib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Healthy Male Participants: A Phase I, Open-Label, Mass-Balance Study. Clin Pharmacol Drug Dev. 2012 Jul;1(3):102-9. doi: 10.1177/2160763X12447303. [Article]
  4. Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
  5. Cotreau MM, Massmanian L, Strahs AL, Slichenmyer W, Vargo DL: The effect of food on the pharmacokinetics of tivozanib hydrochloride. Clin Pharmacol Drug Dev. 2014 Mar;3(2):158-62. doi: 10.1002/cpdd.76. Epub 2013 Oct 30. [Article]
  6. Kim ES: Tivozanib: First Global Approval. Drugs. 2017 Nov;77(17):1917-1923. doi: 10.1007/s40265-017-0825-y. [Article]
  7. Jacob A, Shook J, Hutson TE: Tivozanib, a highly potent and selective inhibitor of VEGF receptor tyrosine kinases, for the treatment of metastatic renal cell carcinoma. Future Oncol. 2020 Oct;16(28):2147-2164. doi: 10.2217/fon-2020-0443. Epub 2020 Jul 21. [Article]
  8. EMC Summary of Product Characteristics: Fotivda (tivozanib hydrochloride monohydrate) oral capsules [Link]
  9. FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
  10. Cancer.org: Key Statistics About Kidney Cancer [Link]
  11. Cayman Chem safety data sheet: Tivozanib hydrate [Link]
  12. EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
  13. AVEO Oncology: Tivozanib hydrochloride pharmacokinetic/pharmacodynamic analysis of blood pressure and soluble vascular endothelial growth factor receptor 2 (sVEGFR2) in patients with advanced renal cell carcinoma [Link]
PubChem Compound
9911830
PubChem Substance
347828149
ChemSpider
8087481
BindingDB
50331095
RxNav
2534233
ChEBI
91327
ChEMBL
CHEMBL1289494
ZINC
ZINC000001489430
PDBe Ligand
AV9
Wikipedia
Tivozanib
PDB Entries
4ase

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentRenal Cell Adenocarcinoma1
3CompletedTreatmentCarcinoma, Renal Cell, Advanced2
2Active Not RecruitingTreatmentProstate Cancer1
2Active Not RecruitingTreatmentRecurrent Fallopian Tube Cancer / Recurrent Primary Peritoneal Cancer / Recurrent, Epithelial Ovarian Cancer1
2CompletedTreatmentColorectal, Cancer1
2CompletedTreatmentGlioblastomas1
2CompletedTreatmentRecurrent Adult Soft Tissue Sarcoma / Stage III Adult Soft Tissue Sarcoma / Stage IV Adult Soft Tissue Sarcoma1
2CompletedTreatmentRenal Cell Adenocarcinoma2
2TerminatedTreatmentBreast Cancer (Triple Negative Breast Cancer (TNBC))1
2TerminatedTreatmentFallopian Tubes Cancer / Ovarian Cancer / Primary Peritoneal Carcinoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral
CapsuleOral0.89 mg/1
CapsuleOral1.34 mg/1
CapsuleOral1340 ?g
CapsuleOral890 ?g
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6821987No2002-04-262022-04-26US flag
US7166722No2003-11-162023-11-16US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)220-233https://store.apolloscientific.co.uk/product/tivozanib
boiling point (°C)550.4 ± 50.0https://www.chemsrc.com/en/cas/475108-18-0_754439.html
water solubility<1g/mLhttps://www.mybiosource.com/inhibitor/tivozanib-av-951/384260
logP4.31https://www.chemsrc.com/en/cas/475108-18-0_754439.html
Caco2 permeability0.5https://www.ema.europa.eu/en/documents/assessment-report/fotivda-epar-public-assessment-report_en.pdf
pKa11.74±0.70https://www.chemicalbook.com/ChemicalProductProperty_EN_CB82484655.htm
Predicted Properties
PropertyValueSource
Water Solubility0.0521 mg/mLALOGPS
logP4.25ALOGPS
logP4.22ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)8.27ChemAxon
pKa (Strongest Basic)5.89ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area107.74 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity120.85 m3·mol-1ChemAxon
Polarizability44.26 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vegf-b-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell ...
Gene Name
FLT1
Uniprot ID
P17948
Uniprot Name
Vascular endothelial growth factor receptor 1
Molecular Weight
150767.185 Da
References
  1. Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
  2. Salgia NJ, Zengin ZB, Pal SK: Tivozanib in renal cell carcinoma: a new approach to previously treated disease. Ther Adv Med Oncol. 2020 May 22;12:1758835920923818. doi: 10.1177/1758835920923818. eCollection 2020. [Article]
  3. FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and ...
Gene Name
KDR
Uniprot ID
P35968
Uniprot Name
Vascular endothelial growth factor receptor 2
Molecular Weight
151525.555 Da
References
  1. Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
  2. Salgia NJ, Zengin ZB, Pal SK: Tivozanib in renal cell carcinoma: a new approach to previously treated disease. Ther Adv Med Oncol. 2020 May 22;12:1758835920923818. doi: 10.1177/1758835920923818. eCollection 2020. [Article]
  3. FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardi...
Gene Name
FLT4
Uniprot ID
P35916
Uniprot Name
Vascular endothelial growth factor receptor 3
Molecular Weight
152755.94 Da
References
  1. Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
  2. Salgia NJ, Zengin ZB, Pal SK: Tivozanib in renal cell carcinoma: a new approach to previously treated disease. Ther Adv Med Oncol. 2020 May 22;12:1758835920923818. doi: 10.1177/1758835920923818. eCollection 2020. [Article]
  3. FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell main...
Gene Name
KIT
Uniprot ID
P10721
Uniprot Name
Mast/stem cell growth factor receptor Kit
Molecular Weight
109863.655 Da
References
  1. Kalathil SG, Wang K, Hutson A, Iyer R, Thanavala Y: Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients. Oncoimmunology. 2020 Sep 30;9(1):1824863. doi: 10.1080/2162402X.2020.1824863. [Article]
  2. Yalcin S, Lacin S: Impact of tivozanib on patient outcomes in treatment of advanced renal cell carcinoma. Cancer Manag Res. 2019 Aug 16;11:7779-7785. doi: 10.2147/CMAR.S206105. eCollection 2019. [Article]
  3. FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor binding
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic...
Gene Name
PDGFRB
Uniprot ID
P09619
Uniprot Name
Platelet-derived growth factor receptor beta
Molecular Weight
123966.895 Da
References
  1. Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE: Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. doi: 10.1200/JCO.2012.47.4940. Epub 2013 Sep 9. [Article]
  2. Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J: The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica. 2007 Jan;92(1):27-34. [Article]
  3. FDA Approved Drug Products: CUBICIN (daptomycin) injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells...
Gene Name
FLT3
Uniprot ID
P36888
Uniprot Name
Receptor-type tyrosine-protein kinase FLT3
Molecular Weight
112902.51 Da
References
  1. Yalcin S, Lacin S: Impact of tivozanib on patient outcomes in treatment of advanced renal cell carcinoma. Cancer Manag Res. 2019 Aug 16;11:7779-7785. doi: 10.2147/CMAR.S206105. eCollection 2019. [Article]
  2. Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE: Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. doi: 10.1200/JCO.2012.47.4940. Epub 2013 Sep 9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chem...
Gene Name
PDGFRA
Uniprot ID
P16234
Uniprot Name
Platelet-derived growth factor receptor alpha
Molecular Weight
122668.46 Da
References
  1. EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Receptor binding
Specific Function
Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. F...
Gene Name
PTK6
Uniprot ID
Q13882
Uniprot Name
Protein-tyrosine kinase 6
Molecular Weight
51833.72 Da
References
  1. EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading...
Gene Name
TEK
Uniprot ID
Q02763
Uniprot Name
Angiopoietin-1 receptor
Molecular Weight
125829.005 Da
References
  1. EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation ...
Gene Name
FGFR1
Uniprot ID
P11362
Uniprot Name
Fibroblast growth factor receptor 1
Molecular Weight
91866.935 Da
References
  1. EMA Assessment Report: Fotivda (tivozanib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including...
Gene Name
MET
Uniprot ID
P08581
Uniprot Name
Hepatocyte growth factor receptor
Molecular Weight
155540.035 Da
References
  1. EMA Assessment Report: Fotivda (tivozanib) oral capsules [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. Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
  2. FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]
  3. EMC Summary of Product Characteristics: Fotivda (tivozanib hydrochloride monohydrate) oral capsules [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: FOTIVDA (tivozanib) capsules, for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Prescribing information indicates that tivozanib is not a substrate for P-glycoprotein, however an in vitro study shows that tivozanib is transported by P-glycoprotein. Clinical significance is unknown.
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. Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice. Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Tivozanib inhibits BCRP in vitro, but this has not been proven in vivo. Clinical significance is unknown.
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Yang D, Kathawala RJ, Chufan EE, Patel A, Ambudkar SV, Chen ZS, Chen X: Tivozanib reverses multidrug resistance mediated by ABCB1 (P-glycoprotein) and ABCG2 (BCRP). Future Oncol. 2014 Aug;10(11):1827-41. doi: 10.2217/fon.13.253. Epub 2013 Dec 3. [Article]
  2. EMC Summary of Product Characteristics: Fotivda (tivozanib hydrochloride monohydrate) oral capsules [Link]

Drug created on October 20, 2016 20:49 / Updated on March 13, 2021 16:57