Identification

Summary

Niraparib is a poly-ADP ribose polymerase inhibitor used to treat recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer responding to platinum based chemotherapy.

Brand Names
Zejula
Generic Name
Niraparib
DrugBank Accession Number
DB11793
Background

Niraparib is an orally active poly (ADP-ribose) polymerase (PARP) inhibitor. By blocking the enzymes responsible for DNA repair, niraparib induces cytotoxicity in cancer cells.6 Niraparib is selective towards PARP-1 and PARP-2.2 First approved by the FDA on March 27, 2017,3 niraparib is used to treat epithelial ovarian, fallopian tube, or primary peritoneal cancer.6 Niraparib was approved by the European Commission on November 16, 2017 7 and by Health Canada on June 27, 2019.8

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 320.396
Monoisotopic: 320.16371128
Chemical Formula
C19H20N4O
Synonyms
  • Niraparib
External IDs
  • MK 4827
  • MK-4827
  • MK-4827 FREE BASE
  • MK4827

Pharmacology

Indication

Niraparib is indicated for the maintenance treatment of adult patients with advanced or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.6,7,8

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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Niraparib mediated cytotoxic effects in tumour cell lines with or without deficiencies in BRCA1/2. Decreased tumour growth was observed in both mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and human patient-derived xenograft tumour models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2.6

In vitro studies suggest that niraparib inhibits dopamine, norepinephrine, and serotonin transporters, which may explain its off-target cardiovascular effects such as increased pulse rate and blood pressure.2

Mechanism of action

Niraparib is a potent and selective inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2.7,8 PARPs play an important role in DNA repair. They recognize and repair cellular DNA damage, such as single-strand breaks (SSBs) and double-strand breaks (DSBs). Different DNA repair pathways exist to repair these DNA damages, including the base excision repair (BER) pathway for SSBs and BRCA-dependent homologous recombination for DSBs.4 If BER is impaired, SSBs accumulate and become DSBs, forcing cells to rely on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining, to repair DNA damages.1 However, some cells can have defective or deficient HR resulting from specific mutations in DNA repair genes, such as BRCA1 and 2.2 Inhibiting PARPs in the presence of HR deficiency leads to a phenomenon called 'synthetic lethality,' whereby the PARP inhibitor impedes BER, leading to genetic instability and cell death.1,2

Selectivity towards PARP-1 and PARP-2 is 100-fold higher than for other PARP family members.2 Niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death.6,7,8

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

Following a single-dose administration of 300 mg niraparib, the mean (±SD) peak plasma concentration (Cmax) was 804 (±403) ng/mL. The exposure (Cmax and AUC) of niraparib increased in a dose-proportional manner with daily doses ranging from 30 mg (0.1 times the approved recommended dose) to 400 mg (1.3 times the approved recommended dose). The accumulation ratio of niraparib exposure following 21 days of repeated daily doses was approximately 2-fold for doses ranging from 30 to 400 mg. The Tmax is about three hours.6

The absolute bioavailability of niraparib is approximately 73%. Food does not appear to affect drug exposure.6

Volume of distribution

The average (±SD) apparent volume of distribution (Vd/F) was 1,220 (±1,114) L. In a population pharmacokinetic analysis, the Vd/F of niraparib was 1,074 L in patients with cancer.6

Protein binding

Niraparib is 83% bound to human plasma proteins.6

Metabolism

Niraparib is primarily metabolized by carboxylesterases (CEs) to form M1, which is a major inactive metabolite. The M1 metabolite can subsequently undergo glucuronidation mediated by UDP-glucuronosyltransferases (UGTs) to form the M10 metabolite.6 In a mass balance study, M1 and M10 were the major circulating metabolites.7 The M1 metabolite can also undergo methylation, monooxygenation, and hydrogenation to form other minor metabolites.5

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Route of elimination

Niraparib is eliminated via multiple pathways, including liver metabolism, hepatobiliary excretion, and renal elimination.8 Following administration of a single oral 300-mg dose of radio-labeled niraparib, the average percent recovery of the administered dose over 21 days was 47.5% (range: 33.4% to 60.2%) in urine and 38.8% (range: 28.3% to 47.0%) in feces. In pooled samples collected over 6 days, unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively.6

Half-life

Following multiple daily doses of 300 mg of niraparib, the mean half-life (t1/2) is 36 hours.6

Clearance

In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 L/h in patients with cancer.6

Adverse Effects
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Toxicity

There is limited information available regarding the acute toxicity profile and overdosage of niraparib.

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
ArticaineThe risk or severity of methemoglobinemia can be increased when Niraparib is combined with Articaine.
BenzocaineThe risk or severity of methemoglobinemia can be increased when Niraparib is combined with Benzocaine.
Benzyl alcoholThe risk or severity of methemoglobinemia can be increased when Niraparib is combined with Benzyl alcohol.
BupivacaineThe risk or severity of methemoglobinemia can be increased when Niraparib is combined with Bupivacaine.
ButacaineThe risk or severity of methemoglobinemia can be increased when Niraparib is combined with Butacaine.
ButambenThe risk or severity of methemoglobinemia can be increased when Niraparib is combined with Butamben.
CapsaicinThe risk or severity of methemoglobinemia can be increased when Niraparib is combined with Capsaicin.
ChloroprocaineThe risk or severity of methemoglobinemia can be increased when Niraparib is combined with Chloroprocaine.
CinchocaineThe risk or severity of methemoglobinemia can be increased when Niraparib is combined with Cinchocaine.
CocaineThe risk or severity of methemoglobinemia can be increased when Niraparib is combined with Cocaine.
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Food Interactions
  • Take at the same time every day.
  • Take with or without food. Food does not affect the absorption of niraparib.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Niraparib hydrochlorideL4JFC1PHCI1038915-64-8YXYDNYFWAFBCAN-PFEQFJNWSA-N
Niraparib tosylate75KE12AY9U1038915-73-9LCPFHXWLJMNKNC-PFEQFJNWSA-N
Niraparib tosylate monohydrate195Q483UZD1613220-15-7ACNPUCQQZDAPJH-FMOMHUKBSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZejulaCapsule100 mgOralGlaxo Smith Kline (Ireland) Limited2020-12-16Not applicableEU flag
ZejulaCapsule100 mg/1OralGlaxoSmithKline LLC2017-03-27Not applicableUS flag
ZejulaCapsule100 mgOralGlaxo Smith Kline (Ireland) Limited2020-12-16Not applicableEU flag
ZejulaTablet100 mgOralGlaxosmithkline IncNot applicableNot applicableCanada flag
ZejulaCapsule100 mgOralGlaxo Smith Kline (Ireland) Limited2020-12-16Not applicableEU flag
ZejulaCapsule100 mgOralGlaxosmithkline Inc2020-01-09Not applicableCanada flag

Categories

ATC Codes
L01XK02 — Niraparib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Phenylpiperidines
Direct Parent
Phenylpiperidines
Alternative Parents
Phenylpyrazoles / Indazoles / Aralkylamines / Benzene and substituted derivatives / Heteroaromatic compounds / Primary carboxylic acid amides / Amino acids and derivatives / Dialkylamines / Azacyclic compounds / Organooxygen compounds
show 2 more
Substituents
Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzopyrazole / Carboxamide group / Carboxylic acid derivative
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
HMC2H89N35
CAS number
1038915-60-4
InChI Key
PCHKPVIQAHNQLW-CQSZACIVSA-N
InChI
InChI=1S/C19H20N4O/c20-19(24)17-5-1-3-15-12-23(22-18(15)17)16-8-6-13(7-9-16)14-4-2-10-21-11-14/h1,3,5-9,12,14,21H,2,4,10-11H2,(H2,20,24)/t14-/m1/s1
IUPAC Name
2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
SMILES
NC(=O)C1=CC=CC2=CN(N=C12)C1=CC=C(C=C1)[C@@H]1CCCNC1

References

General References
  1. Chen A: PARP inhibitors: its role in treatment of cancer. Chin J Cancer. 2011 Jul;30(7):463-71. doi: 10.5732/cjc.011.10111. [Article]
  2. Heo YA, Duggan ST: Niraparib: A Review in Ovarian Cancer. Target Oncol. 2018 Aug;13(4):533-539. doi: 10.1007/s11523-018-0582-1. [Article]
  3. Ison G, Howie LJ, Amiri-Kordestani L, Zhang L, Tang S, Sridhara R, Pierre V, Charlab R, Ramamoorthy A, Song P, Li F, Yu J, Manheng W, Palmby TR, Ghosh S, Horne HN, Lee EY, Philip R, Dave K, Chen XH, Kelly SL, Janoria KG, Banerjee A, Eradiri O, Dinin J, Goldberg KB, Pierce WF, Ibrahim A, Kluetz PG, Blumenthal GM, Beaver JA, Pazdur R: FDA Approval Summary: Niraparib for the Maintenance Treatment of Patients with Recurrent Ovarian Cancer in Response to Platinum-Based Chemotherapy. Clin Cancer Res. 2018 Sep 1;24(17):4066-4071. doi: 10.1158/1078-0432.CCR-18-0042. Epub 2018 Apr 12. [Article]
  4. 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]
  5. van Andel L, Zhang Z, Lu S, Kansra V, Agarwal S, Hughes L, Tibben MM, Gebretensae A, Lucas L, Hillebrand MJX, Rosing H, Schellens JHM, Beijnen JH: Human mass balance study and metabolite profiling of (14)C-niraparib, a novel poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor, in patients with advanced cancer. Invest New Drugs. 2017 Dec;35(6):751-765. doi: 10.1007/s10637-017-0451-2. Epub 2017 Mar 16. [Article]
  6. FDA Approved Drug Products: ZEJULA (niraparib) capsules, for oral use (September 2022) [Link]
  7. EMA Approved Drug Products: Zejula (niraparib) Oral Capsules [Link]
  8. Health Canada Approved Drug Products: ZEJULA (niraparib) Oral Capsules or Tablets [Link]
PubChem Compound
24958200
PubChem Substance
347828142
ChemSpider
24531930
BindingDB
50316226
RxNav
1918231
ChEBI
176844
ChEMBL
CHEMBL1094636
ZINC
ZINC000043206370
PharmGKB
PA166131610
PDBe Ligand
3JD
Wikipedia
Niraparib
PDB Entries
4r6e / 7f43 / 7kk5 / 7kkp

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentOvarian Cancer1
4Not Yet RecruitingTreatmentAdvanced Ovarian Cancer / Epithelial Ovarian Cancer / Ovarian Cancer / Stage III Ovarian Cancer1
4RecruitingPreventionAdult Patients With Platinum-sensitive, Relapsed, High Grade Serous Epithelial Ovarian Cancer1
3Active Not RecruitingTreatmentCastration Resistant Prostatic Cancer1
3Active Not RecruitingTreatmentNeoplasms, Ovarian1
3Active Not RecruitingTreatmentNeoplasms, Ovarian / Ovarian Cancer1
3Active Not RecruitingTreatmentNeoplastic Disease1
3Active Not RecruitingTreatmentRecurrent Ovarian Carcinoma1
3CompletedTreatmentNeoplasms, Ovarian / Platinum Sensitive Ovarian Cancer1
3Not Yet RecruitingTreatmentBiliary Tract Neoplasms1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral100 mg
CapsuleOral100 mg/1
TabletOral100 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8859562No2014-10-142031-08-04US flag
US8143241No2012-03-272027-08-12US flag
US8071579No2011-12-062027-08-12US flag
US8071623No2011-12-062030-03-22US flag
US8436185No2013-05-072029-04-24US flag
US11091459No2021-08-172038-03-27US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)463https://file.medchemexpress.com/batch_PDF/HY-10619/Niraparib-SDS-MedChemExpress.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.0149 mg/mLALOGPS
logP2.45ALOGPS
logP2.47Chemaxon
logS-4.3ALOGPS
pKa (Strongest Acidic)14.03Chemaxon
pKa (Strongest Basic)10.08Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area72.94 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity94.92 m3·mol-1Chemaxon
Polarizability36.4 Å3Chemaxon
Number of Rings4Chemaxon
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

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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. Heo YA, Duggan ST: Niraparib: A Review in Ovarian Cancer. Target Oncol. 2018 Aug;13(4):533-539. doi: 10.1007/s11523-018-0582-1. [Article]
  2. FDA Approved Drug Products: ZEJULA (niraparib) capsules, for oral use (September 2022) [Link]
  3. EMA Approved Drug Products: Zejula (niraparib) Oral Capsules [Link]
  4. Health Canada Approved Drug Products: ZEJULA (niraparib) Oral Capsules or Tablets [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. Heo YA, Duggan ST: Niraparib: A Review in Ovarian Cancer. Target Oncol. 2018 Aug;13(4):533-539. doi: 10.1007/s11523-018-0582-1. [Article]
  2. FDA Approved Drug Products: ZEJULA (niraparib) capsules, for oral use (September 2022) [Link]
  3. EMA Approved Drug Products: Zejula (niraparib) Oral Capsules [Link]
  4. Health Canada Approved Drug Products: ZEJULA (niraparib) Oral Capsules or Tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Carboxylic ester hydrolase activity
Specific Function
Not Available
Gene Name
CES1A1a
Uniprot ID
Q6LAP9
Uniprot Name
Carboxylesterase
Molecular Weight
1908.25 Da
References
  1. FDA Approved Drug Products: ZEJULA (niraparib) capsules, for oral use (September 2022) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
Curator comments
Niraparib weakly induces CYP1A2 in vitro.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA Approved Drug Products: ZEJULA (niraparib) capsules, for oral use (September 2022) [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. Health Canada Approved Drug Products: ZEJULA (niraparib) Oral Capsules or Tablets [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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. FDA Approved Drug Products: ZEJULA (niraparib) capsules, for oral use (September 2022) [Link]
  2. EMA Approved Drug Products: Zejula (niraparib) Oral Capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Curator comments
Niraparib inhibits MATE1 with IC50 of 0.18 microM. Niraparib M1 metabolite is a substrate of MATE1.
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. FDA Approved Drug Products: ZEJULA (niraparib) capsules, for oral use (September 2022) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Curator comments
Niraparib inhibits MATE2 with IC50 of ≤0.14 microM. Niraparib M1 metabolite is a substrate of MATE2.
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. FDA Approved Drug Products: ZEJULA (niraparib) capsules, for oral use (September 2022) [Link]
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: ZEJULA (niraparib) capsules, for oral use (September 2022) [Link]
  2. EMA Approved Drug Products: Zejula (niraparib) Oral Capsules [Link]

Drug created at October 20, 2016 20:48 / Updated at December 04, 2022 18:48