Identification

Name
Talazoparib
Accession Number
DB11760
Description

Talazoparib was approved by the FDA for use in germline BRCA mutated, HER2 negative, locally advanced or metastatic breast cancer on October 16, 2018 under the trade name Talzenna 3. Talzenna was granted approval based on the results of the EMBRACA trial in which talazoparib resulted in a mean 8.6 months progression-free survival time versus physician's choice chemotherapy which resulted in 5.6 months progression-free survival.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 380.359
Monoisotopic: 380.119715421
Chemical Formula
C19H14F2N6O
Synonyms
  • Talazoparib
External IDs
  • BMN 673
  • BMN-673
  • LT-673

Pharmacology

Indication

Talazoparib is indicated for the treatment of deleterious or suspected deleterious germline BRCA mutated, HER2 negative locally advanced or metastatic breast cancer in adults Label.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Talazoparib prevents PARP-mediated repair of DNA damage in cancer cells, allowing accumulation of damage and PARP-DNA complexes Label. Repair related errors by error prone secondary repair pathways may also contribute to the cytotoxicity of talazoparib 2.

Mechanism of action

Talazoparib binds to and inhibits PARP1 and PARP2 at the NAD+ binding site with a Ki of 1.2 and 0.87 nM, respectively 1. The inhibitory effect on PAR synthesis has an EC50 of 2.51 nM.

TargetActionsOrganism
APoly [ADP-ribose] polymerase 1
inhibitor
Humans
APoly [ADP-ribose] polymerase 2
inhibitor
Humans
Absorption

Talzenna capsules have a reach peak plasma concentration in 1-2 h Label. If taken with a high fat meal, Cmax decreases by 43%, Tmax increases by 1-4 h, and no change occurs in AUC.

Volume of distribution

Talazoparib has a mean apparent volume of distribution of 420 L Label.

Protein binding

Talazoparib is 74% bound to plasma proteins and independent of drug concentration Label.

Metabolism

Talazoparib is metabolized via mono-oxidation, dehydrogenation, cysteine conjugation of a mono-desfluoro metabolite, and glucuronide conjugation Label. The overall contribution of metabolism to talazoparib elimination is minimal.

Route of elimination

64.7% of talazoparib is excreted in the urine with 54.6% as unchanged drug Label. 19.7% is eliminated in the feces with 13.6% as unchanged drug.

Half-life

The mean terminal plasma half life of Talzenna capsules is 90 h with a standard deviation of 58 h Label.

Clearance

The mean apparent oral clearance of talazoparib is 6.45 L/h with an inter-individual variability of 31.1% Label. Apparent oral clearance is reduced by 14.4% in patients with mild renal impairment while mild hepatic impairment has no effect. No data is available in patients with moderate to severe renal or hepatic impairment.

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

Talazoparib is clastogenic due to its pharmacological mechanism Label. Talazoparib does not appear to be mutagenic and no data is available on carcinogenicity.

In repeat-dose toxicity studies up to 3-months duration at doses ≥0.04 mg/kg/day in rats and ≥0.01 mg/kg/day in dogs resulted in decreased organ weights, luminal cellular debris, reduced sperm, and degeneration/atrophy in the testis and epididymis Label. These doses were equivalent to approximately 1.0 times and 0.2 times normal human exposure. Follicular atresia of the ovary was observed in rats at doses ≥1 mg/kg/day, equivalent to 9.5 times normal human exposure. While no fertility data exists these results suggest a potential for reduced fertility due to talazoparib exposure.

Affected organisms
Not Available
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
AbemaciclibAbemaciclib may decrease the excretion rate of Talazoparib which could result in a higher serum level.
AfatinibThe serum concentration of Talazoparib can be increased when it is combined with Afatinib.
AlectinibAlectinib may decrease the excretion rate of Talazoparib which could result in a higher serum level.
AmbrisentanThe serum concentration of Talazoparib can be increased when it is combined with Ambrisentan.
AmiodaroneThe serum concentration of Talazoparib can be increased when it is combined with Amiodarone.
ApalutamideThe serum concentration of Talazoparib can be decreased when it is combined with Apalutamide.
ApixabanThe serum concentration of Talazoparib can be increased when it is combined with Apixaban.
AsunaprevirThe serum concentration of Talazoparib can be increased when it is combined with Asunaprevir.
AvatrombopagAvatrombopag may decrease the excretion rate of Talazoparib which could result in a higher serum level.
BaricitinibBaricitinib may decrease the excretion rate of Talazoparib which could result in a higher serum level.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take at the same time every day.
  • Take with or without food.

Products

Product Ingredients
IngredientUNIICASInChI Key
Talazoparib tosylate02WK9U5NZC1373431-65-2QUQKKHBYEFLEHK-QNBGGDODSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TalzennaCapsule1 mg/1OralPfizer Laboratories Div Pfizer Inc2018-10-26Not applicableUS flag
TalzennaCapsule0.25 mg/1OralExcella GmbH & Co. KG2018-10-26Not applicableUS flag
TalzennaCapsule1 mgOralPfizer Canada UlcNot applicableNot applicableCanada flag
TalzennaCapsule0.25 mg/1OralPfizer Laboratories Div Pfizer Inc2018-10-26Not applicableUS flag
TalzennaCapsule1 mg/1OralU.S. Pharmaceuticals2018-10-26Not applicableUS flag
TalzennaCapsule0.25 mgOralPfizer Canada UlcNot applicableNot applicableCanada flag
TalzennaCapsule1 mg/1OralExcella GmbH & Co. KG2018-10-26Not applicableUS flag
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

ATC Codes
L01XX60 — Talazoparib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylquinolines. These are heterocyclic compounds containing a quinoline moiety substituted with a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Phenylquinolines
Direct Parent
Phenylquinolines
Alternative Parents
Phthalazinones / Secondary alkylarylamines / Pyridazinones / Fluorobenzenes / Aralkylamines / Aryl fluorides / Triazoles / Heteroaromatic compounds / Lactams / Azacyclic compounds
show 4 more
Substituents
1,2,4-triazole / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Fluorobenzene
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
9QHX048FRV
CAS number
1207456-01-6
InChI Key
HWGQMRYQVZSGDQ-HZPDHXFCSA-N
InChI
InChI=1S/C19H14F2N6O/c1-27-18(22-8-23-27)15-16(9-2-4-10(20)5-3-9)24-13-7-11(21)6-12-14(13)17(15)25-26-19(12)28/h2-8,15-16,24H,1H3,(H,26,28)/t15-,16-/m1/s1
IUPAC Name
(11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(1-methyl-1H-1,2,4-triazol-5-yl)-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5,7,9(13)-tetraen-4-one
SMILES
CN1N=CN=C1[[email protected]@H]1[[email protected]](NC2=C3C1=NNC(=O)C3=CC(F)=C2)C1=CC=C(F)C=C1

References

Synthesis Reference

Wang B, Chu D, Feng Y, Shen Y, Aoyagi-scharber M, Post LE. Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016;59(1):335-57.

General References
  1. Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE: Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-te trahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016 Jan 14;59(1):335-57. doi: 10.1021/acs.jmedchem.5b01498. Epub 2015 Dec 23. [PubMed:26652717]
  2. Javle M, Curtin NJ: The role of PARP in DNA repair and its therapeutic exploitation. Br J Cancer. 2011 Oct 11;105(8):1114-22. doi: 10.1038/bjc.2011.382. [PubMed:21989215]
  3. Talazoparib FDA Approval [Link]
PubChem Compound
44819241
PubChem Substance
347828114
ChemSpider
28637772
BindingDB
50084621
RxNav
2099704
ChEMBL
CHEMBL3137320
ZINC
ZINC000072318110
PDBe Ligand
2YQ
Wikipedia
Talazoparib
PDB Entries
4pjt / 4pjv / 4und
FDA label
Download (549 KB)
MSDS
Download (25 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentBRCA 1 Gene Mutation / BRCA 2 Gene Mutation / Neoplasms, Breast1
3Active Not RecruitingTreatmentOvarian Cancer1
3RecruitingTreatmentMCRPC1
2Active Not RecruitingTreatmentATM Gene Mutation / ATR Gene Mutation / BARD1 Gene Mutation / BRCA1 Gene Mutation / Brca2 Gene Mutation / BRIP1 Gene Mutation / CHEK1 Gene Mutation / CHEK2 Gene Mutation / FANCA Gene Mutation / FANCC Gene Mutation / FANCD2 Gene Mutation / FANCF Gene Mutation / FANCM Gene Mutation / NBN Gene Mutation / PALB2 Gene Mutation / RAD51 Gene Mutation / RAD51B Gene Mutation / RAD54L Gene Mutation / Recurrent Squamous Cell Lung Carcinoma / RPA1 Gene Mutation / Stage IV Squamous Cell Lung Carcinoma AJCC v71
2Active Not RecruitingTreatmentAvelumab in Combination With Talazoparib Will be Investigated in Patients With Locally Advanced (Primary or Recurrent) or Metastatic Solid Tumors1
2Active Not RecruitingTreatmentBreast Adenocarcinoma / Deleterious BRCA1 Gene Mutation / Deleterious BRCA2 Gene Mutation / HER2/Neu Negative / Invasive Breast Carcinoma1
2Active Not RecruitingTreatmentEarly Breast Cancer1
2Active Not RecruitingTreatmentGenes, BRCA 1 / Locally Advanced or Metastatic Solid Tumors1
2Active Not RecruitingTreatmentMetastatic Castration Resistant Prostate Cancer (mCRPC) / Squamous Cell Carcinoma of the Head and Neck (SCCHN)1
2Active Not RecruitingTreatmentProstate Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral0.25 MG
CapsuleOral0.25 mg/1
CapsuleOral1 MG
CapsuleOral1 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9820985No2017-11-212029-07-27US flag
US8012976No2011-09-062029-10-19US flag
US8735392No2014-05-272031-10-20US flag
US8420650No2013-04-162029-07-27US flag
US10189837No2019-01-292031-10-20US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.101 mg/mLALOGPS
logP2.93ALOGPS
logP2.11ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)9.48ChemAxon
pKa (Strongest Basic)1.66ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area84.2 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity111.27 m3·mol-1ChemAxon
Polarizability35.82 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This ...
Gene Name
PARP1
Uniprot ID
P09874
Uniprot Name
Poly [ADP-ribose] polymerase 1
Molecular Weight
113082.945 Da
References
  1. Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE: Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-te trahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016 Jan 14;59(1):335-57. doi: 10.1021/acs.jmedchem.5b01498. Epub 2015 Dec 23. [PubMed:26652717]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Nad+ adp-ribosyltransferase activity
Specific Function
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This ...
Gene Name
PARP2
Uniprot ID
Q9UGN5
Uniprot Name
Poly [ADP-ribose] polymerase 2
Molecular Weight
66205.31 Da
References
  1. Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE: Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-te trahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016 Jan 14;59(1):335-57. doi: 10.1021/acs.jmedchem.5b01498. Epub 2015 Dec 23. [PubMed:26652717]

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
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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

Drug created on October 20, 2016 14:45 / Updated on June 12, 2020 11:42

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