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
Thumb
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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.

TargetActionsOrganism
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.
DrugInteraction
Darbepoetin alfaThe risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Niraparib.
ErythropoietinThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Niraparib.
Methoxy polyethylene glycol-epoetin betaThe risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Niraparib.
PeginesatideThe risk or severity of Thrombosis can be increased when Peginesatide is combined with Niraparib.
Interactions
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Food Interactions
  • Take at the same time every day.
  • Take with or without food.

Products

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 mgOralGlaxo Smith Kline (Ireland) Limited2020-12-16Not applicableEU flag
ZejulaCapsule100 mgOralGlaxosmithkline Inc2020-01-09Not applicableCanada flag
ZejulaCapsule100 mgOralGlaxo Smith Kline (Ireland) Limited2020-12-16Not applicableEU flag
ZejulaCapsule100 mg/1OralGlaxoSmithKline LLC2017-03-27Not applicableUS flag

Categories

ATC Codes
L01XX54 — 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. FDA approval [Link]
  3. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors [Link]
  4. FDA label [Link]
PubChem Compound
24958200
PubChem Substance
347828142
ChemSpider
24531930
BindingDB
50316226
RxNav
1918231
ChEMBL
CHEMBL1094636
ZINC
ZINC000043206370
PharmGKB
PA166131610
PDBe Ligand
3JD
Wikipedia
Niraparib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
4r6e / 7kk5 / 7kkp

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentOvarian Cancer1
4Not Yet RecruitingPreventionAdult Patients With Platinum-sensitive, Relapsed, High Grade Serous Epithelial Ovarian Cancer1
3Active Not RecruitingTreatmentBRCA1 Gene Mutation / Brca2 Gene Mutation / Carcinoma of Breast / Human Epidermal Growth Factor 2 Negative Carcinoma of Breast / Neoplasms, Breast / Neoplasms, Ovarian1
3Active Not RecruitingTreatmentNeoplasms, Ovarian / Ovarian Cancer2
3Active Not RecruitingTreatmentNeoplasms, Ovarian / Platinum Sensitive Ovarian Cancer1
3Not Yet RecruitingTreatmentOvarian Cancer1
3RecruitingTreatmentCastration-Resistant Prostatic Cancer1
3RecruitingTreatmentMetastatic Castrate Sensitive Prostate Cancer1
3RecruitingTreatmentNeoplasms1
3RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral
CapsuleOral100 mg
CapsuleOral100 mg/1
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

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0149 mg/mLALOGPS
logP2.45ALOGPS
logP2.47ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)14.03ChemAxon
pKa (Strongest Basic)10.1ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area72.94 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity94.92 m3·mol-1ChemAxon
Polarizability36.41 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

Drugtargets
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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]
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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Yes
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
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
Receptor binding
Specific Function
Plays an important role in the degradation of dermatan and keratan sulfates.
Gene Name
GUSB
Uniprot ID
P08236
Uniprot Name
Beta-glucuronidase
Molecular Weight
74731.46 Da

Drug created on October 20, 2016 20:48 / Updated on June 12, 2021 01:52