Talazoparib

Identification

Summary

Talazoparib is a poly-ADP ribose polymerase inhibitor used to treat HER2-, BRCA mutated locally advanced or metastatic breast cancer and HRR gene-mutated metastatic castration-resistant prostate cancer.

Brand Names
Talzenna
Generic Name
Talazoparib
DrugBank Accession Number
DB11760
Background

Talazoparib is an inhibitor of mammalian polyadenosine 5’-diphosphoribose polymerases (PARPs), enzymes responsible for regulating essential cellular functions, such as DNA transcription and DNA repair.4

Developed by Pfizer, talazoparib was first approved by the FDA in October 2018 2 and by the EMA in June 2019.5 It was approved by Health Canada in September 2020.6 Talazoparib is currently used in the treatment of BRCA-mutated breast cancer and HRR-mutated prostate cancer.4,6,7

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 380.359
Monoisotopic: 380.119715421
Chemical Formula
C19H14F2N6O
Synonyms
  • Talazoparib
External IDs
  • BMN 673
  • BMN-673
  • BMN673
  • LT 006673
  • LT-00673
  • LT-673
  • MDV-3800

Pharmacology

Indication

Talazoparib is indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. This indication is approved by the FDA, EMA, and Health Canada.4,6,7

In the US, talazoparib is also indicated in combination with enzalutamide for the treatment of adult patients with HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC).4

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatHrr gene-mutated (hrrm) metastatic castration-resistant prostate cancer (mcrpc)Regimen in combination with: Enzalutamide (DB08899)•••••••••••••••••
Treatment ofLocally advanced breast cancer•••••••••••••••••
Treatment ofMetastatic breast cancer•••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Talazoparib is a cytotoxic and anti-tumour agent. In vitro, talazoparib caused cytotoxicity in cancer cell lines that harboured defects in DNA repair genes, including BRCA1 and BRCA2. Talazoparib mediated anti-tumour effects on patient-derived xenograft breast cancer models bearing mutated BRCA1 or mutated BRCA2 or wild type BRCA1 and BRCA2.2,4

Mechanism of action

Poly(ADP-ribose) polymerases (PARPs) are multifunctional enzymes involved in essential cellular functions, such as DNA transcription and DNA repair. PARPs recognize and repair DNA single-strand breaks (SSBs) via the base excision repair (BER) pathway. DNA double-strand breaks (DSBs) are repaired via homologous recombination by tumour suppressor proteins encoded by BRCA1 and BRCA2.3,2

Talazoparib is a potent inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2.4 In vitro, talazoparib binds to PARP-1 and -2 isoforms with similar affinity.2 Inhibition of the BER pathway by talazoparib leads to the accumulation of unrepaired SSBs, which leads to the formation of DSBs, which is the most toxic form of DNA damage. While BRCA-dependent homologous recombination can repair DSBs in normal cells, this repair pathway is defective in cells with BRCA1/2 mutations, such as certain tumour cells.[A246015] Inhibition of PARP in cancer cells with BRCA mutations leads to genomic instability and apoptotic cell death. This end result is also referred to as synthetic lethality, a phenomenon where the combination of two defects - inhibition of PARP activity and loss of DSB repair by HR - that are otherwise benign when alone leads to detrimental results.1,3 By inhibiting PARP, talazoparib increases the formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis.4

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

After administration of talazoparib 1 mg orally once daily, the mean [% coefficient of variation (CV%)] AUC and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was 208 (37%) ng x hr/mL and 16.4 (32%) ng/mL, respectively. The mean (CV%) steady-state Ctrough was 3.53 (61%) ng/mL.4 Steady state was reached within two to three weeks of therapy.2 The Tmax ranges from one to two hours.4

A high-fat, high-calorie food increased the mean Cmax by 46% and the median Tmax from one to four hours, without affecting the AUC. 4

Volume of distribution

The mean apparent volume of distribution of talazoparib is 420 L.4

Protein binding

In vitro, the protein binding of talazoparib is 74% and is independent of talazoparib concentration.4

Metabolism

Talazoparib undergoes minimal hepatic metabolism. The metabolic pathways include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro talazoparib, and glucuronide conjugation.4

Route of elimination

The major route of elimination is renal excretion. Approximately 68.7% of the total administered radiolabeled dose of talazoparib was recovered in urine, where 54.6% of that dose was in the form of an unchanged drug. About 19.7% of the drug was recovered in feces, with 13.6% of the dose is unchanged.4

Half-life

The mean terminal plasma half-life (±standard deviation) is 90 (±58) hours in patients with cancer.2,4

Clearance

The mean apparent oral clearance is 6.45 L/h. The inter-subject variability is 31%.4

Adverse Effects
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Toxicity

There is no information available regarding the acute toxicity (LD50) of talazoparib. There is no specific treatment in the event of talazoparib overdose, and symptoms of overdose have not been established. In the event of an overdose, discontinue treatment with talazoparib, consider gastric decontamination, follow general supportive measures, and treat symptomatically.4

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
AbemaciclibThe serum concentration of Talazoparib can be increased when it is combined with Abemaciclib.
AbrocitinibThe serum concentration of Talazoparib can be increased when it is combined with Abrocitinib.
AdagrasibThe serum concentration of Talazoparib can be increased when it is combined with Adagrasib.
AfatinibThe serum concentration of Talazoparib can be increased when it is combined with Afatinib.
AlectinibThe serum concentration of Talazoparib can be increased when it is combined with Alectinib.
Food Interactions
  • Take at the same time every day.
  • Take with or without food. A high-fat, high-calorie meal decreases Cmax and delays Tmax, but not to a clinically significant extent.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Talazoparib tosylate02WK9U5NZC1373431-65-2QUQKKHBYEFLEHK-QNBGGDODSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TalzennaCapsule0.25 mgOralPfizer Europe Ma Eeig2021-02-11Not applicableEU flag
TalzennaCapsule0.1 mg/1OralPfizer Laboratories Div Pfizer Inc2023-06-21Not applicableUS flag
TalzennaCapsule0.75 mg/1OralPfizer Laboratories Div Pfizer Inc2022-01-31Not applicableUS flag
TalzennaCapsule1 mgOralPfizer Europe Ma Eeig2021-02-11Not applicableEU flag
TalzennaCapsule0.25 mg/1OralPfizer Laboratories Div Pfizer Inc2018-10-26Not applicableUS flag

Categories

ATC Codes
L01XK04 — 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
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. 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]
  2. Hoy SM: Talazoparib: First Global Approval. Drugs. 2018 Dec;78(18):1939-1946. doi: 10.1007/s40265-018-1026-z. [Article]
  3. Bochum S, Berger S, Martens UM: Olaparib. Recent Results Cancer Res. 2018;211:217-233. doi: 10.1007/978-3-319-91442-8_15. [Article]
  4. FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]
  5. Pfizer Press Release: European Commission Approves TALZENNA® (talazoparib) for Patients with Inherited (Germline) BRCA-Mutated Locally Advanced or Metastatic Breast Cancer [Link]
  6. Health Canada Approved Drug Products: TALZENNA (Talazoparib) Oral Capsules [Link]
  7. EMA Approved Drug Products: TALZENNA (talazoparib) Oral Capsules [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 / 7kk3 / 7kkn

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentMCRPC1
3Active Not RecruitingTreatmentProstate Cancer1
3CompletedTreatmentBRCA 1 Gene Mutation / BRCA 2 Gene Mutation / Breast Neoplasms1
3RecruitingTreatmentAdvanced Malignant Neoplasm / Non-Small Cell Lung Cancer (NSCLC) / Ovarian Cancer / Solid Tumors / Urothelial Cancer1
3TerminatedTreatmentOvarian Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral0.1 mg/1
CapsuleOral0.25 mg/1
CapsuleOral0.35 mg/1
CapsuleOral0.5 mg/1
CapsuleOral0.75 mg/1
CapsuleOral1 mg/1
CapsuleOral1.453 mg
CapsuleOral0.25 mg
CapsuleOral1 mg
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
US10780088No2020-09-222029-07-27US flag

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/MSsplash10-001i-0009000000-1eff4346bf91d0ab9a06
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-056r-0009000000-d6852a92f125c7601cbd
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0009000000-ae3f4f2e7eed281bfe79
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0009000000-ba83b1b6b5be43e9cf9d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-01ti-0069000000-89f9f29acfc5ca983f20
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-002r-3349000000-673477b0c4c2c7f71c47
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-194.31976
predicted
DeepCCS 1.0 (2019)
[M+H]+196.71535
predicted
DeepCCS 1.0 (2019)
[M+Na]+202.62785
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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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]
  2. FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]
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]
  2. FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [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. Bruin MAC, Sonke GS, Beijnen JH, Huitema ADR: Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology. Clin Pharmacokinet. 2022 Dec;61(12):1649-1675. doi: 10.1007/s40262-022-01167-6. Epub 2022 Oct 11. [Article]
  2. Elmeliegy M, Lang I, Smolyarchuk EA, Chung CH, Plotka A, Shi H, Wang D: Evaluation of the effect of P-glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours. Br J Clin Pharmacol. 2020 Apr;86(4):771-778. doi: 10.1111/bcp.14178. Epub 2020 Jan 7. [Article]
  3. FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]
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
References
  1. Bruin MAC, Sonke GS, Beijnen JH, Huitema ADR: Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology. Clin Pharmacokinet. 2022 Dec;61(12):1649-1675. doi: 10.1007/s40262-022-01167-6. Epub 2022 Oct 11. [Article]
  2. Elmeliegy M, Lang I, Smolyarchuk EA, Chung CH, Plotka A, Shi H, Wang D: Evaluation of the effect of P-glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours. Br J Clin Pharmacol. 2020 Apr;86(4):771-778. doi: 10.1111/bcp.14178. Epub 2020 Jan 7. [Article]
  3. FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]

Drug created at October 20, 2016 20:45 / Updated at July 18, 2023 22:56