Niraparib

{{Short description|Anti-cancer medication}} {{Use dmy dates|date=February 2020}} {{Infobox drug | image = Niraparib.svg | image_class = skin-invert-image | width = | alt = | caption = Above: molecular structure of niraparib Below: 3D representation of a niraparib molecule | image2 = Niraparib 3D.png | image_class2 = bg-transparent | pronounce = {{IPAc-en|n|ɪ|ˈ|r|æ|p|ə|r|ɪ|b}}<br />{{respell|nih|RAP|uh|rib}} | tradename = Zejula | Drugs.com = {{Drugs.com|monograph|niraparib}} | MedlinePlus = a617007 | DailyMedID = Niraparib | pregnancy_AU = D | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth | class = | ATC_prefix = L01 | ATC_suffix = XK02 | ATC_supplemental =  | legal_AU = S4 | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = / Schedule D<ref>{{cite web | title=Summary Basis of Decision (SBD) for Zejula | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00450&lang=en | access-date=29 May 2022}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = <ref name="Zejula SmPC">{{cite web | title=Zejula 100 mg hard capsules - Summary of Product Characteristics (SmPC) | website=(emc) | url=https://www.medicines.org.uk/emc/product/8828 | access-date=17 January 2021}}</ref> | legal_US = Rx-only | legal_US_comment = <ref name="Zejula FDA label">{{cite web | title=Zejula- niraparib capsule | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c15c7b7e-4b7f-4489-bbbc-884caeee0669 | access-date=17 January 2021}}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="Zejula EPAR">{{cite web | title=Zejula EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/zejula | access-date=17 January 2021}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> | legal_UN =  | legal_UN_comment = | legal_status =

| IUPAC_name = 2-[4-[(3''S'')-3-Piperidyl]phenyl]indazole-7-carboxamide | C = 19 | H = 20 | N = 4 | O = 1 | SMILES = c1cc2cn(nc2c(c1)C(=O)N)c3ccc(cc3)[C@@H]4CCCNC4 | StdInChI = 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 | StdInChI_comment = | StdInChIKey = PCHKPVIQAHNQLW-CQSZACIVSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = 0.7–1.1 | sol_units = | specific_rotation = }}

'''Niraparib''', sold under the brand name '''Zejula''', is an anti-cancer medication used for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer.<ref name="Zejula FDA label" /><ref name="Zejula EPAR" /><ref name="FDA" /> It is taken by mouth.<ref name="Zejula FDA label" /><ref name="Zejula EPAR" /> It is a PARP inhibitor.

The most common side effects include nausea (feeling sick), thrombocytopenia (low blood platelet counts), tiredness and weakness, anemia (low red blood cell counts), constipation, vomiting, abdominal (belly) pain, neutropenia (low levels of neutrophils, a type of white blood cell), insomnia (difficulty sleeping), headache, lack of appetite, diarrhea, dyspnea (difficulty breathing), hypertension (high blood pressure), back pain, dizziness, cough, joint pain, hot flushes and decrease in white blood cells.<ref name="Zejula EPAR" />

Niraparib was approved for medical use in the United States and in the European Union in 2017.<ref name="Zejula EPAR" /><ref name="FDA PR">{{cite press release | title=FDA approves maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers | website=U.S. Food and Drug Administration (FDA) | date=27 March 2017 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-maintenance-treatment-recurrent-epithelial-ovarian-fallopian-tube-or-primary-peritoneal | access-date=17 January 2021}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}} {{PD-notice}}</ref><ref>{{cite web | title=Drug Trials Snapshots: Zejula | website=U.S. Food and Drug Administration (FDA) | date=27 March 2017 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-zejula | access-date=17 January 2021}} {{PD-notice}}</ref>

==Medical uses== Niraparib is indicated for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.<ref name="FDA" />

In October 2019, the indication for niraparib was expanded to include people with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)-positive status.<ref name="FDA 20191023">{{cite web | title=FDA approves niraparib for HRD-positive advanced ovarian cancer | website=U.S. Food and Drug Administration (FDA) | date=23 October 2019 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-hrd-positive-advanced-ovarian-cancer | archive-url=https://web.archive.org/web/20191214081914/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-hrd-positive-advanced-ovarian-cancer | url-status=dead | archive-date=14 December 2019 | access-date=17 January 2021}} {{PD-notice}}</ref> HRD is defined by either a deleterious or suspected deleterious BRCA mutation, or genomic instability in patients with disease progression greater than six months after response to the last platinum-based chemotherapy.<ref name="FDA 20191023" />

In April 2020, the indication for niraparib was expanded to include the maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.<ref>{{cite web | title=FDA approves niraparib for first-line maintenance of advanced ovarian | website=U.S. Food and Drug Administration (FDA) | date=29 April 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer | archive-url=https://web.archive.org/web/20200530121332/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer | url-status=dead | archive-date=30 May 2020 | access-date=17 January 2021}} {{PD-notice}}</ref>

In the European Union, niraparib is indicated: as monotherapy for the maintenance treatment of adults with advanced epithelial (FIGO Stages III and IV) high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy; and as monotherapy for the maintenance treatment of adults with platinum sensitive relapsed high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum based chemotherapy.<ref name="Zejula EPAR" />

==Contraindications== No contraindications are listed in the prescribing information.<ref name="Zejula FDA label" />

==Side effects== The most common side effects in studies were low blood cell counts, namely thrombocytopenia (in 61% of patients, severe in 29%), anemia (in 50%, severe in 25%) and neutropenia (in 30%, severe in 20%). Other, mostly mild to moderate side effects included nausea, fatigue, and constipation. In a study running over 250 days (median), 15% of patients had to permanently discontinue niraparib due to adverse effects.<ref name="Zejula FDA label" />

== Interactions ==

No clinical interaction studies have been performed. The potential for interactions with other drugs is low as niraparib and its main metabolite M1 do not significantly interact with any of the important cytochrome P450 liver enzymes ''in vitro''. Niraparib, but not M1, is transported by P-glycoprotein and BCRP, but does not significantly inhibit them. Neither niraparib nor M1 significantly interact with any of the other important transporter proteins.<ref name="Zejula FDA label" />

==Pharmacology== ===Mechanism of action=== {{further|PARP inhibitor#Mechanism of action}} Niraparib is an inhibitor of the enzymes PARP1 and PARP2.<ref name="AHFS">{{cite web | title=Niraparib Monograph for Professionals | publisher=American Society of Health-System Pharmacists | date=22 September 2020 | url=https://www.drugs.com/monograph/niraparib.html | access-date=17 January 2021}}</ref>

===Pharmacokinetics=== [[File:Niraparib metabolite.svg|thumb|The inactive main metabolite M1 is the carboxylic acid derivative of niraparib.<ref name="Andel">{{cite journal | vauthors = van Andel L, Zhang Z, Lu S, Kansra V, Agarwal S, Hughes L, Tibben MM, Gebretensae A, Lucas L, Hillebrand MJ, Rosing H, Schellens JH, Beijnen JH | display-authors = 6 | title = 14C-niraparib, a novel poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor, in patients with advanced cancer | journal = Investigational New Drugs | volume = 35 | issue = 6 | pages = 751–765 | date = December 2017 | pmid = 28303528 | pmc = 5694528 | doi = 10.1007/s10637-017-0451-2 }}</ref>]]

73% of ingested niraparib is absorbed in the gut,<ref name="van Andel">{{cite journal | vauthors = van Andel L, Rosing H, Zhang Z, Hughes L, Kansra V, Sanghvi M, Tibben MM, Gebretensae A, Schellens JH, Beijnen JH | display-authors = 6 | title = 14C-microtracer and therapeutic dose in cancer patients | journal = Cancer Chemotherapy and Pharmacology | volume = 81 | issue = 1 | pages = 39–46 | date = January 2018 | pmid = 29043410 | pmc = 5754411 | doi = 10.1007/s00280-017-3455-x }}</ref> and it reaches highest blood plasma concentrations after about three hours, independently of food intake. In the circulation, 83% of the substance are bound to plasma proteins. It is inactivated by carboxylesterases to the main metabolite M1, the carboxylic acid derivative,<ref name="Andel" /> which is subsequently glucuronidated.<ref name="Zejula FDA label" />

The mean biological half-life is 36 hours. 47.5% of the substance are found in the urine and 38.8% in the feces. Unmetabolised niraparib accounts for 11% in the urine and 19% in the feces.<ref name="Andel" />

==Chemistry== The drug is used in form of the salt niraparib tosylate monohydrate, which is white to off-white, non-hygroscopic crystals.<ref name="Zejula FDA label" /><ref name="AHFS" />

==Studies== A 2012 study in a cell line found that PARP inhibitors exhibit cytotoxic effects not based solely on their enzymatic inhibition of PARP, but by their trapping of PARP on damaged DNA, and the strength of this trapping activity was ordered niraparib >> olaparib >> veliparib.<ref>{{cite journal | vauthors = Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y | display-authors = 6 | title = Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors | journal = Cancer Research | volume = 72 | issue = 21 | pages = 5588–99 | date = November 2012 | pmid = 23118055 | pmc = 3528345 | doi = 10.1158/0008-5472.CAN-12-2753 }}</ref>

== History == Niraparib was granted fast track designation by the US Food and Drug Administration (FDA), and Tesaro submitted a new drug application in 2016.<ref>{{cite web | url=http://www.esmo.org/Oncology-News/Niraparib-Receives-FDA-Fast-Track-Designation-for-the-Treatment-of-Recurrent-Platinum-Sensitive-Ovarian-Fallopian-Tube-or-Primary-Peritoneal-Cancer | title=Niraparib Receives FDA Fast Track Designation for the Treatment of Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer | work=The European Society for Medical Oncology (ESMO) | date=5 September 2016 | access-date=2 February 2017 | archive-date=4 August 2020 | archive-url=https://web.archive.org/web/20200804171312/https://www.esmo.org/oncology-news/Niraparib-Receives-FDA-Fast-Track-Designation-for-the-Treatment-of-Recurrent-Platinum-Sensitive-Ovarian-Fallopian-Tube-or-Primary-Peritoneal-Cancer | url-status=dead }}</ref> It was approved on 27 March 2017 in the US,<ref name="FDA">{{cite web|url=https://www.fda.gov/drugs/resources-information-approved-drugs/niraparib-zejula|archive-url=https://web.archive.org/web/20190915173225/https://www.fda.gov/drugs/resources-information-approved-drugs/niraparib-zejula|url-status=dead|archive-date=15 September 2019|publisher=U.S. Food and Drug Administration (FDA) |title=Niraparib (Zejula)|date=30 March 2017}} {{PD-notice}}</ref> and approved in European Union on 16 November 2017.<ref>{{cite web | url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004249/human_med_002192.jsp&mid=WC0b01ac058001d124 | title=Zejula | work=European Medicines Agency | date=2018-09-17 | access-date=29 May 2018 | archive-date=9 August 2018 | archive-url=https://web.archive.org/web/20180809153310/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F004249%2Fhuman_med_002192.jsp&mid=WC0b01ac058001d124 | url-status=dead }}</ref>

In a study with 553 patients, progression-free survival (PFS) for patients with a deleterious or suspected deleterious BRCA mutation in the germline was 21.0 months under niraparib therapy, as compared to 5.5 months under placebo. Patients without such a mutation had a PFS of 9.3 months under niraparib versus 3.9 months under placebo.<ref name="FDA" /><ref name=Tesaro201606>{{cite web | first = Ben | last = Adams | name-list-style = vanc | url = http://www.fiercebiotech.com/biotech/tesaro-s-parp-ovarian-cancer-drug-hits-phiii-goal-prepares-to-file | title = Tesaro's PARP ovarian cancer drug hits PhIII goal; prepares to file. | date = 29 June 2016 | work = Fierce Biotech }}</ref>

The US Food and Drug Administration (FDA) granted the application for niraparib fast track, priority review, breakthrough therapy, and orphan drug designations.<ref name="FDA" />

== References == {{reflist}}

==External links== * {{cite web | title=Niraparib tosylate monohydrate | work=NCI Drug Dictionary | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/niraparib-tosylate-monohydrate }} * {{cite web | title=Niraparib tosylate monohydrate | website=National Cancer Institute | date=14 April 2017 | url=https://www.cancer.gov/about-cancer/treatment/drugs/niraparibtosylatemonohydrate }}

Category:Indazolecarboxamides Category:Drugs developed by GSK plc Category:Orphan drugs Category:PARP inhibitors Category:Piperidines