Talazoparib

Identification

Summary

Talazoparib is a poly-ADP ribose polymerase inhibitor used to treat HER2-, BRCA mutated locally advanced or metastatic breast cancer.

Brand Names

Talzenna

Generic Name

Talazoparib

DrugBank Accession Number

DB11760

Background

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

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Talazoparib (DB11760)

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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.

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Associated Conditions

• Locally Advanced Breast Cancer (LABC)
• Metastatic Breast Cancer

Contraindications & Blackbox Warnings

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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.

Target	Actions	Organism
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

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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.

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abemaciclib	Abemaciclib may decrease the excretion rate of Talazoparib which could result in a higher serum level.
Afatinib	The serum concentration of Talazoparib can be increased when it is combined with Afatinib.
Alectinib	Alectinib may decrease the excretion rate of Talazoparib which could result in a higher serum level.
Ambrisentan	The serum concentration of Talazoparib can be increased when it is combined with Ambrisentan.
Amiodarone	The serum concentration of Talazoparib can be increased when it is combined with Amiodarone.
Apalutamide	The serum concentration of Talazoparib can be decreased when it is combined with Apalutamide.
Apixaban	The serum concentration of Talazoparib can be increased when it is combined with Apixaban.
Arsenic trioxide	The serum concentration of Talazoparib can be increased when it is combined with Arsenic trioxide.
Asunaprevir	The serum concentration of Talazoparib can be increased when it is combined with Asunaprevir.
Avanafil	Avanafil may decrease the excretion rate of Talazoparib which could result in a higher serum level.

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Food Interactions

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

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Talazoparib tosylate	02WK9U5NZC	1373431-65-2	QUQKKHBYEFLEHK-QNBGGDODSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Talzenna	Capsule	1 mg/1	Oral	Excella GmbH & Co. KG	2018-10-26	Not applicable
Talzenna	Capsule	0.25 mg	Oral	Pfizer Europe Ma Eeig	2021-02-11	Not applicable
Talzenna	Capsule	0.25 mg	Oral	Pfizer Canada Ulc	Not applicable	Not applicable
Talzenna	Capsule	1 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2018-10-26	Not applicable
Talzenna	Capsule	0.25 mg	Oral	Pfizer Europe Ma Eeig	2021-02-11	Not applicable
Talzenna	Capsule	0.25 mg/1	Oral	Excella GmbH & Co. KG	2018-10-26	Not applicable
Talzenna	Capsule	0.25 mg	Oral	Pfizer Europe Ma Eeig	2021-02-11	Not applicable
Talzenna	Capsule	1 mg	Oral	Pfizer Europe Ma Eeig	2021-02-11	Not applicable
Talzenna	Capsule	0.25 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2018-10-26	Not applicable
Talzenna	Capsule	1 mg/1	Oral	U.S. Pharmaceuticals	2018-10-26	Not applicable

Categories

ATC Codes

L01XX60 — Talazoparib

• L01XX — Other antineoplastic agents
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• BCRP/ABCG2 Substrates
• Enzyme Inhibitors
• Narrow Therapeutic Index Drugs
• P-glycoprotein substrates
• P-glycoprotein substrates with a Narrow Therapeutic Index
• Poly(ADP-ribose) Polymerase Inhibitors
• Pyridazines

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 / Organooxygen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives

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Substituents

1,2,4-triazole / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Fluorobenzene / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Lactam / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Phenylquinoline / Phthalazine / Phthalazinone / Pyridazine / Pyridazinone / Secondary aliphatic/aromatic amine / Secondary amine

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

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[C@@H]1[C@H](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. [Article]
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. [Article]
3. Talazoparib FDA Approval [Link]

External Links

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 / 7kk3 / 7kkn

FDA label

Download (549 KB)

MSDS

Download (25 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Ovarian Cancer	1
3	Completed	Treatment	BRCA 1 Gene Mutation / BRCA 2 Gene Mutation / Neoplasms, Breast	1
3	Recruiting	Treatment	MCRPC	1
3	Recruiting	Treatment	Prostate Cancer	1
2	Active Not Recruiting	Treatment	ATM 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 v7	1
2	Active Not Recruiting	Treatment	Avelumab in Combination With Talazoparib Will be Investigated in Patients With Locally Advanced (Primary or Recurrent) or Metastatic Solid Tumors	1
2	Active Not Recruiting	Treatment	Breast Adenocarcinoma / Deleterious BRCA1 Gene Mutation / Deleterious BRCA2 Gene Mutation / HER2/Neu Negative / Invasive Breast Carcinoma	1
2	Active Not Recruiting	Treatment	Genes, BRCA 1 / Locally Advanced or Metastatic Solid Tumors	1
2	Active Not Recruiting	Treatment	Prostate Cancer	1
2	Not Yet Recruiting	Treatment	Advanced Breast Cancer / Breast Cancer	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral
Capsule	Oral	0.25 mg
Capsule	Oral	0.25 mg/1
Capsule	Oral	1 mg/1
Capsule	Oral	1 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9820985	No	2017-11-21	2029-07-27
US8012976	No	2011-09-06	2029-10-19
US8735392	No	2014-05-27	2031-10-20
US8420650	No	2013-04-16	2029-07-27
US10189837	No	2019-01-29	2031-10-20

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.101 mg/mL	ALOGPS
logP	2.93	ALOGPS
logP	2.11	ChemAxon
logS	-3.6	ALOGPS
pKa (Strongest Acidic)	9.48	ChemAxon
pKa (Strongest Basic)	1.66	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	84.2 Å2	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	111.27 m3·mol-1	ChemAxon
Polarizability	35.82 Å3	ChemAxon
Number of Rings	5	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details1. Poly [ADP-ribose] polymerase 1

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. [Article]

Details2. Poly [ADP-ribose] polymerase 2

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. [Article]

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Drug created on October 20, 2016 20:45 / Updated on February 21, 2021 18:53