Niraparib

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 PARP inhibitor developed by Tesaro to treat ovarian cancer. FDA approval on March 2017.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Niraparib (DB11793)

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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 recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy

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Associated Conditions

• Fallopian Tubes Cancer
• Ovarian Cancer (Epithelial)
• Primary Peritoneal Cancer

Contraindications & Blackbox Warnings

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Pharmacodynamics

Cardiovascular Effects: Niraparib has the potential to cause effects on pulse rate and blood pressure in patients receiving the recommended dose, which may be related to pharmacological inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT). In the NOVA study, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the niraparib and placebo arms, respectively.
Cardiac Electrophysiology The potential for QTc prolongation with niraparib was evaluated in a randomized, placebo-controlled trial in cancer patients (367 patients on niraparib and 179 patients on placebo). No large changes in the mean QTc interval (>20 ms) were detected in the trial following the treatment of niraparib 300 mg once daily.

Mechanism of action

Niraparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that 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. Increased niraparib-induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2.

Target	Actions	Organism
APoly [ADP-ribose] polymerase 1	antagonist	Humans
APoly [ADP-ribose] polymerase 2	antagonist	Humans

Absorption

The absolute bioavailability of niraparib is approximately 73%. Following oral administration of niraparib, peak plasma concentration, Cmax, is reached within 3 hours. Concomitant administration of a high fat meal (800-1,000 calories with approximately 50% of total caloric content of the meal from fat) did not significantly affect the pharmacokinetics of niraparib.
Following a single-dose administration of 300 mg niraparib, the mean (±SD) peak plasma concentration (Cmax) was 804 (± 403) ng/mL. The systemic exposures (Cmax and AUC) of niraparib increased in a dose proportional manner with daily doses ranging 30 mg (0.1 times the approved recommended dosage) to 400 mg (1.3 times the approved recommended dosage). The accumulation ratio of niraparib exposure following 21 days of repeated daily doses was approximately 2 fold for doses ranging from 30 mg to 400 mg.

Volume of distribution

The average (±SD) apparent volume of distribution (Vd/F) was 1220 (±1114) L.

Protein binding

Niraparib is 83.0% bound to human plasma proteins.

Metabolism

Niraparib is metabolized primarily by carboxylesterases (CEs) to form a major inactive metabolite, which subsequently undergoes glucuronidation.

Route of elimination

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.

Half-life

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

Clearance

the apparent total clearance (CL/F) of niraparib was 16.2 L/h in cancer patients.

Adverse Effects

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Toxicity

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.

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

Drug	Interaction
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Darbepoetin alfa	The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Niraparib.
Erythropoietin	The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Niraparib.
Methoxy polyethylene glycol-epoetin beta	The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Niraparib.
Peginesatide	The risk or severity of Thrombosis can be increased when Peginesatide is combined with Niraparib.

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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
Niraparib hydrochloride	L4JFC1PHCI	1038915-64-8	YXYDNYFWAFBCAN-PFEQFJNWSA-N
Niraparib tosylate	75KE12AY9U	1038915-73-9	LCPFHXWLJMNKNC-PFEQFJNWSA-N
Niraparib tosylate monohydrate	195Q483UZD	1613220-15-7	ACNPUCQQZDAPJH-FMOMHUKBSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Zejula	Capsule	100 mg	Oral	Glaxo Smith Kline (Ireland) Limited	2020-12-16	Not applicable
Zejula	Capsule	100 mg/1	Oral	GlaxoSmithKline LLC	2017-03-27	Not applicable
Zejula	Capsule	100 mg	Oral	Glaxo Smith Kline (Ireland) Limited	2020-12-16	Not applicable
Zejula	Capsule	100 mg	Oral	Glaxo Smith Kline (Ireland) Limited	2020-12-16	Not applicable
Zejula	Capsule	100 mg	Oral	Glaxosmithkline Inc	2020-01-09	Not applicable

Categories

ATC Codes

L01XX54 — Niraparib

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

Drug Categories

• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Enzyme Inhibitors
• Heterocyclic Compounds, Fused-Ring
• Narrow Therapeutic Index Drugs
• Poly(ADP-ribose) Polymerase Inhibitors
• Pyrazoles

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 / Organic oxides / Hydrocarbon derivatives

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Substituents

Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzopyrazole / Carboxamide group / Carboxylic acid derivative / Heteroaromatic compound / Hydrocarbon derivative / Indazole / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organonitrogen compound / Organooxygen compound / Phenylpiperidine / Phenylpyrazole / Primary carboxylic acid amide / Pyrazole / Secondary aliphatic amine / Secondary amine

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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. FDA approval [Link]
3. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors [Link]
4. FDA Approved Drug Products: Zejula (niraparib) capsules for oral use [Link]

External Links

PubChem Compound

24958200

PubChem Substance

347828142

ChemSpider

24531930

BindingDB

50316226

RxNav

1918231

ChEMBL

CHEMBL1094636

ZINC

ZINC000043206370

PharmGKB

PA166131610

PDBe Ligand

3JD

Wikipedia

Niraparib

PDB Entries

4r6e / 7kk5 / 7kkp

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Ovarian Cancer	1
4	Not Yet Recruiting	Prevention	Adult Patients With Platinum-sensitive, Relapsed, High Grade Serous Epithelial Ovarian Cancer	1
4	Not Yet Recruiting	Treatment	BRCA1/2 Wild-type, Advanced-stage, Low-risk, Primary Ovarian Cancer Patients	1
3	Active Not Recruiting	Treatment	Castration Resistant Prostatic Cancer	1
3	Active Not Recruiting	Treatment	Neoplasms, Ovarian	1
3	Active Not Recruiting	Treatment	Neoplasms, Ovarian / Ovarian Cancer	1
3	Active Not Recruiting	Treatment	Neoplasms, Ovarian / Platinum Sensitive Ovarian Cancer	1
3	Completed	Treatment	BRCA 1 Gene Mutation / Brca2 Gene Mutation / Breast Carcinoma / Human Epidermal Growth Factor 2 Negative Carcinoma of Breast / Neoplasms, Breast / Neoplasms, Ovarian	1
3	Not Yet Recruiting	Treatment	Fallopian Tubes Cancer / Malignant Peritoneal Neoplasm / Ovarian Cancer	1
3	Recruiting	Treatment	Metastatic Castrate Sensitive Prostate Cancer	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	100 mg
Capsule	Oral	100 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8859562	No	2014-10-14	2031-08-04
US8143241	No	2012-03-27	2027-08-12
US8071579	No	2011-12-06	2027-08-12
US8071623	No	2011-12-06	2030-03-22
US8436185	No	2013-05-07	2029-04-24
US11091459	No	2018-03-27	2038-03-27

Properties

State

Not Available

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0149 mg/mL	ALOGPS
logP	2.45	ALOGPS
logP	2.47	ChemAxon
logS	-4.3	ALOGPS
pKa (Strongest Acidic)	14.03	ChemAxon
pKa (Strongest Basic)	10.1	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	72.94 Å2	ChemAxon
Rotatable Bond Count	3	ChemAxon
Refractivity	94.92 m3·mol-1	ChemAxon
Polarizability	36.41 Å3	ChemAxon
Number of Rings	4	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

Antagonist

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. PARP inhibitor, MK-4827, shows anti-tumor activity in first trial in humans [Link]

Details2. Poly [ADP-ribose] polymerase 2

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

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. PARP inhibitor, MK-4827, shows anti-tumor activity in first trial in humans [Link]

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Drug created at October 20, 2016 20:48 / Updated at January 21, 2022 19:16