Ribociclib

{{Short description|Chemical compound}} {{Use dmy dates|date=July 2023}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | image = Ribociclib skeletal.svg | image_class = skin-invert-image | alt = | caption = | image2 = Ribociclib-from-xtal-3D-bs-17.png | image_class2 = bg-transparent

| pronounce = {{IPAc-en|ˌ|r|aɪ|b|oʊ|ˈ|s|aɪ|k|l|ɪ|b}}<br />{{respell|RY|boh|SYE|klib}} | tradename = Kisqali | Drugs.com = {{Drugs.com|monograph|ribociclib-succinate}} | MedlinePlus = a617008 | DailyMedID = Ribociclib | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_category= | routes_of_administration = By mouth | class = Antineoplastic, CDK inhibitor | ATC_prefix = L01 | ATC_suffix = EF02

| legal_AU = S4 | legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-chemical-entities-australia-2017 | access-date=9 April 2023}}</ref><ref>{{cite web | title=Prescription medicines and biologicals: TGA annual summary 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-and-biologicals-tga-annual-summary-2017 | access-date=31 March 2024}}</ref> | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00352 | title=Regulatory Decision Summary for Kisqali | date=2 March 2018 | website=Health Canada | access-date=8 June 2024}}</ref> | legal_DE =  | legal_NZ =  | legal_UK =  | legal_US = Rx-only | legal_US_comment = <ref name="Kisqali FDA label">{{cite web | title=Kisqali- ribociclib tablet, film coated | website=DailyMed | date=4 May 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aaeaef94-f3f5-4367-8ea2-b181d7be2da8 | access-date=9 July 2023}}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="Kisqali EPAR">{{cite web | title=Kisqali EPAR | website=European Medicines Agency (EMA) | date=31 March 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/kisqali | access-date=9 July 2023}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> | legal_UN =  | legal_status =

| IUPAC_name = 7-Cyclopentyl-''N'',''N''-dimethyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}-7''H''-pyrrolo[2,3-d]pyrimidine-6-carboxamide | C=23 | H=30 | N=8 | O=1 | SMILES = CN(C)C(=O)c1cc2cnc(nc2n1C3CCCC3)Nc4ccc(cn4)N5CCNCC5 | StdInChI=1S/C23H30N8O/c1-29(2)22(32)19-13-16-14-26-23(28-21(16)31(19)17-5-3-4-6-17)27-20-8-7-18(15-25-20)30-11-9-24-10-12-30/h7-8,13-15,17,24H,3-6,9-12H2,1-2H3,(H,25,26,27,28) | StdInChIKey = RHXHGRAEPCAFML-UHFFFAOYSA-N }}

'''Ribociclib''', sold under the brand name '''Kisqali''', is a medication used for the treatment of certain kinds of breast cancer.<ref name="Kisqali FDA label" /> Ribociclib is a kinase inhibitor.<ref name="Kisqali FDA label" /> It was developed by Novartis and Astex Pharmaceuticals.<ref>{{cite press release|url=https://www.novartis.com/news/media-releases/novartis-lee011-ribociclib-granted-fda-priority-review-first-line-treatment-hrher2-advanced-breast-cancer |title=Novartis LEE011 (ribociclib) granted FDA Priority Review for first-line treatment of HR+/HER2- advanced breast cancer|publisher=Novartis|date=1 November 2016|access-date=27 January 2017|archive-date=25 September 2018|archive-url=https://web.archive.org/web/20180925040140/https://www.novartis.com/news/media-releases/novartis-lee011-ribociclib-granted-fda-priority-review-first-line-treatment|url-status=live}}</ref>

The most common side effects include infections, low levels of white blood cells, headache, cough, nausea (feeling sick), vomiting, diarrhea, constipation, tiredness, hair loss and rash.<ref name="Kisqali EPAR" />

Ribociclib was approved for medical use in the United States in March 2017,<ref name="Kisqali approval package">{{cite web | title=Kisqali (ribociclib) Tablets | website=U.S. Food and Drug Administration (FDA) | date=28 March 2017 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209092Orig1s000TOC.cfm | access-date=9 July 2023}}</ref><ref name="kf">{{cite web | title=FDA Clears Novartis Kisqali for Combination Breast Cancer Therapy | website=Genetic Engineering and Biotechnology News | date=14 March 2017 | url=https://www.genengnews.com/news/fda-clears-novartis-kisqali-for-combination-breast-cancer-therapy/ | access-date=9 July 2023}}</ref> in the European Union in August 2017,<ref name="Kisqali EPAR" /><ref name="EPAR">{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004213/WC500233997.pdf|title=Kisqali: EPAR – Product Information|publisher=European Medicines Agency|date=31 August 2017|access-date=8 September 2017|archive-date=18 June 2018|archive-url=https://web.archive.org/web/20180618071049/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004213/WC500233997.pdf}}</ref> and in the United Kingdom in February 2021.<ref name=":0">{{Cite press release|title=Thousands of breast cancer patients to have routine access to NICE-approved drug combination|url=https://www.nice.org.uk/news/article/thousands-of-breast-cancer-patients-to-have-routine-access-to-nice-approved-drug-combination|access-date=8 March 2021|website=NICE|archive-date=15 March 2021|archive-url=https://web.archive.org/web/20210315075727/https://www.nice.org.uk/news/article/thousands-of-breast-cancer-patients-to-have-routine-access-to-nice-approved-drug-combination}}</ref><ref>{{Cite news|date=26 February 2021|title=Life-extending drug for incurable breast cancer approved for NHS use|url=http://www.theguardian.com/society/2021/feb/26/life-extending-drug-ribociclib-incurable-breast-cancer-approved-for-nhs|access-date=8 March 2021|website=The Guardian }}</ref>

==Medical uses== In the United States, it is indicated for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy; or fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy in postmenopausal women or in men.<ref name="Kisqali FDA label" /><ref name="Kisqali approval package" />

In the European Union, it is indicated for the treatment of women with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)‑negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy.<ref name="Kisqali EPAR" /> In pre‑ or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone‑releasing hormone (LHRH) agonist.<ref name="Kisqali EPAR" />

In September 2024, the US Food and Drug Administration (FDA) expanded the indication for ribociclib, in combination with an aromatase inhibitor, for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence.<ref name="FDA ribociclib 20240917" /> Additionally, the FDA approved the ribociclib and letrozole co-pack for the same indication.<ref name="FDA ribociclib 20240917">{{cite web | title=FDA approves ribociclib with an aromatase inhibitor and ribociclib and letrozole co-pack for early high-risk breast cancer | website=U.S. Food and Drug Administration (FDA) | date=17 September 2024 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ribociclib-aromatase-inhibitor-and-ribociclib-and-letrozole-co-pack-early-high-risk-0 | archive-url=https://web.archive.org/web/20240917210316/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ribociclib-aromatase-inhibitor-and-ribociclib-and-letrozole-co-pack-early-high-risk-0 | archive-date=17 September 2024 | access-date=15 October 2024}} {{PD-notice}}</ref>

In November 2024, the European Commission expanded the indication of ribociclib, in combination with an aromatase inhibitor, for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer at high risk of recurrence.<ref name="Kisqali EPAR" /><ref>{{cite web | title=Kisqali - opinion on variation to marketing authorisation | website=European Medicines Agency (EMA) | date=17 October 2024 | url=https://www.ema.europa.eu/en/medicines/human/variation/kisqali | access-date=27 November 2024}}</ref><ref>{{Cite press release |title=Novartis Kisqali receives European Commission approval in a broad population of patients with HR+/HER2- early breast cancer at high risk of recurrence |url=https://www.novartis.com/news/media-releases/novartis-kisqali-receives-european-commission-approval-broad-population-patients-hrher2-early-breast-cancer-high-risk-recurrence |access-date=2024-11-27 |website=Novartis }}</ref>

==Side effects== The most common side effects in studies were decreased blood cell counts, mainly neutropenia (in 75% of patients, as compared to 5% under placebo), but also anemia (18% vs. 5%). Gastrointestinal disorders were also common, for example nausea (52% vs. 29%) and diarrhea (35% vs. 22%), as was alopecia (33% vs. 16%). The drug also increases the QT interval and liver enzymes (alanine transaminase, aspartate transaminase).<ref name="Kisqali FDA label" /><ref name="EPAR" />

The most common side effects include infections, low levels of white blood cells, headache, cough, nausea, vomiting, diarrhoea, constipation, tiredness, hair loss and rash.<ref name="Kisqali EPAR" /> The most common severe side effects include infections, low levels of red and white blood cells, vomiting, abnormal blood tests for liver function and low levels of phosphate in the blood (hypophosphataemia).<ref name="Kisqali EPAR" />

== Interactions == As ribociclib is mainly metabolized by the liver enzyme CYP3A4, inhibitors of this enzyme increase its concentrations in the body and could potentiate side effects and toxicity. Examples of such inhibitors include ketoconazole and similar antifungal drugs, ritonavir, clarithromycin, as well as grapefruit. Conversely, drugs that induce CYP3A4, such as rifampicin and St John's Wort, can decrease ribociclib concentrations.<ref name="Kisqali FDA label" /><ref name="EPAR" />

Ribociclib itself is a moderate to strong CYP3A4 inhibitor and can increase concentrations of other drugs that share this metabolism, as has been shown with midazolam. It also inhibits a number of transporter proteins and could thus theoretically interfere with the transport of other drugs in the body. It could also amplify QT prolongation of other drugs such as antiarrhythmics, clarithromycin, and haloperidol.<ref name="Kisqali FDA label" /><ref name="EPAR" />

==Pharmacology== ===Pharmacodynamics=== {{further|CDK inhibitor}} Cyclin-dependent kinases (CDKs) 4 and 6 are enzymes that have been shown to promote cell division and multiplication in both normal and cancer cells. Many cancer cells have shown abnormalities that increase the activity of CDK, leading to the inactivation of certain tumor suppressor genes.<ref name=Samson2014>{{cite journal | vauthors = Samson K |title=LEE011 CDK Inhibitor Showing Early Promise in Drug-Resistant Cancers |journal=Oncology Times |volume=36 |issue=3 |year=2014 |pages=39–40 |doi=10.1097/01.COT.0000444043.33304.c1 }}</ref><ref>{{cite journal | vauthors = Kim S, Loo A, Chopra R, Caponigro G, Huang A, Vora S, Parasuraman S, Howard S, Keen N, Sellers W, Brain C |title=Abstract PR02: LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6- Reactivating Rb in cancer |journal=Molecular Cancer Therapeutics |volume=12 |issue=11_Supplement |year=2014 |pages=PR02 |doi=10.1158/1535-7163.TARG-13-PR02 }}</ref>

When used in combination with other drugs such as an ALK inhibitor or an MEK inhibitor, ribociclib has been shown to have a synergistic effect, resulting in improved responses.<ref>{{cite journal |vauthors=Sosman JA, Kittaneh M, Lolkema MP, Postow MA, Schwartz G, Franklin C, Matano A, Bhansali S, Parasuraman S, Kim K |year=2014 |title=A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with ''NRAS''-mutant melanoma: Early encouraging clinical activity |journal=Journal of Clinical Oncology |volume=32 |issue=15 Suppl |page=9009 |doi=10.1200/jco.2014.32.15_suppl.9009 |url=http://hwmaint.meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/9009 |access-date=14 January 2017 |archive-date=7 October 2015 |archive-url=https://web.archive.org/web/20151007043635/http://hwmaint.meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/9009 |url-access=subscription }}</ref><ref>{{cite journal | vauthors = Wood AC, Krytska K, Ryles H, Sano R, Li N, King F, Smith T, Tuntland T, Kim S, Caponigro G, He YQ |title=Abstract 1000: Combination CDK4/6 and ALK inhibition demonstrates on-target synergy against neuroblastoma |journal=Cancer Research |volume=74 |issue=19 Supplement |year=2014 |page=1000 |doi=10.1158/1538-7445.AM2014-1000 }}</ref> Again, this is likely a result of "crosstalk" between signaling pathways. Simply blocking one pathway in cancer tumorigenesis can sometimes result in "tumor compensation", where the tumor compensates for the blocked signaling pathway by utilizing other pathways to survive. By blocking several pathways at once, it is thought that the tumor is less able to compensate, and a greater anti-tumor response is often observed. Utilizing ribociclib in combination with other agents has been shown to reduce the development of resistance to these agents.<ref name=Samson2014/>

===Pharmacokinetics=== The percentage of ribociclib absorbed in the gut has not been determined. Highest blood plasma levels are reached after one to four hours; and after repeated dosage, steady state concentrations are reached after about eight days. Food intake has no effect on absorption rates. When in the bloodstream, about 70% of ribociclib is bound to plasma proteins.<ref name="Kisqali FDA label" /><ref name="EPAR" />

The substance is mainly metabolized by CYP3A4 and subsequently by various phase II enzymes, resulting in a large number of metabolites. Those with highest blood plasma concentrations in humans are called CCI284 (an unspecified ''N''-hydroxylation product), LEQ803 (the ''N''-demethylation product) and M1 (a glucuronide). All metabolites have negligible clinical activity.<ref name="Kisqali FDA label" /><ref name="EPAR" />

Ribociclib has a slight tendency to accumulate in the body. It is eliminated with an average biological half-life of 32 hours, mostly (69%) via the feces, but also (23%) via the urine. The unchanged drug accounts for 17% of the substance in the feces and 12% of the substance in the urine, the rest being metabolites.<ref name="Kisqali FDA label" /><ref name="EPAR" />

==Chemistry== Ribociclib is used in form of its succinate salt. It is a slightly hygroscopic yellow to brown crystalline powder that is soluble in aqueous acids.<ref name="AssessmentReport">{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004213/WC500233999.pdf|title=Kisqali: EPAR – Public assessment report|publisher=European Medicines Agency|date=31 August 2017|access-date=8 September 2017|archive-date=18 June 2018|archive-url=https://web.archive.org/web/20180618071303/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004213/WC500233999.pdf}}</ref>

== History == Ribociclib demonstrated a clinical benefit on overall survival across all three phase III trials of the MONALEESA clinical program with different endocrine therapy partners, regardless of menopausal status or line of therapy.<ref>{{cite journal | vauthors = Slamon DJ, Fasching PA, Hurvitz S, Chia S, Crown J, Martín M, Barrios CH, Bardia A, Im SA, Yardley DA, Untch M, Huang CS, Stroyakovskiy D, Xu B, Moroose RL, Loi S, Visco F, Bee-Munteanu V, Afenjar K, Fresco R, Taran T, Chakravartty A, Zarate JP, Lteif A, Hortobagyi GN | title = Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy ''versus'' endocrine therapy alone in patients with HR+/HER2- early breast cancer | journal = Therapeutic Advances in Medical Oncology | volume = 15 | article-number = 17588359231178125 | date = May 2023 | pmid = 37275963 | pmc = 10233570 | doi = 10.1177/17588359231178125 }}</ref> The European Society of Medical Oncology (ESMO) assigned the highest score on the 'Magnitude of Clinical Benefit Scale' for ribociclib.<ref>{{Cite web |title=ESMO-Magnitude of Clinical Benefit Scale |url=https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-for-solid-tumours/esmo-mcbs-scorecards/scorecard-158-1 |access-date=19 October 2021 |website=ESMO}}</ref>

In the clinical trial relevant for the drug's approval, ribociclib significantly improved progression-free survival, that is, the time span the cancer did not get worse. For participants receiving placebo plus letrozole, progression-free survival was 16 months on average, while under ribociclib plus letrozole, progression-free survival was 25 months as of the January 2017 analysis.<ref name="EPAR" />

In October 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended a change to the terms of the marketing authorization for ribociclib to add the adjuvant treatment of people with hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer, at high risk of disease recurrence.<ref name="EMA Kisqali variation 20241018" /> The marketing authorization holder is Novartis Europharm Limited.<ref name="EMA Kisqali variation 20241018">{{Cite web |date=18 October 2024 |title=Kisqali - opinion on variation to marketing authorisation |url=https://www.ema.europa.eu/en/medicines/human/variation/kisqali |access-date=22 October 2024 |website=European Medicines Agency (EMA) }}</ref> In November 2024, the European Commission expanded the marketing authorization to include the use of ribociclib in combination with an aromatase inhibitor for the adjuvant treatment of patients with hormone receptor -positive, human epidermal growth factor receptor 2 -negative early breast cancer at high risk of recurrence.<ref>{{cite press release | title=Novartis Kisqali receives European Commission approval in a broad population of patients with HR+/HER2- early breast cancer at high risk of recurrence | publisher=Novartis | via=GlobeNewswire | date=27 November 2024 | url=https://www.globenewswire.com/news-release/2024/11/27/2987957/0/en/Novartis-Kisqali-receives-European-Commission-approval-in-a-broad-population-of-patients-with-HR-HER2-early-breast-cancer-at-high-risk-of-recurrence.html | access-date=22 March 2025}}</ref>

== References == {{reflist}}

Category:Protein kinase inhibitors Category:Carboxamides Category:CYP1A1 inhibitors Category:CYP3A4 inhibitors Category:Disubstituted pyridines Category:Drugs developed by Novartis Category:Pyrimidines Category:1-Piperazinyl compounds Category:Cyclopentyl compounds Category:CDK inhibitors