Ribociclib: Difference between revisions

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{{Short description|Chemical compound}}
{{Use dmy dates|date=July 2023}}
{{Infobox drug
{{Infobox drug
⚫
| IUPAC_name = 7-Cyclopentyl-''N'',''N''-dimethyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}-7''H''-pyrrolo[2,3-d]pyrimidine-6-carboxamide
| image = Ribociclib skeletal.svg
| image = Ribociclib skeletal.svg
| alt =
| alt =
| caption =
| caption =
| image2 = Ribociclib-from-xtal-3D-bs-17.png

<!-- Clinical data -->
<!-- Clinical data -->
| pronounce =
| pronounce =
| tradename = Kisqali
| tradename = Kisqali
| Drugs.com = {{Drugs.com|parent|kisqali}}
| Drugs.com = {{Drugs.com|monograph|ribociclib-succinate}}
| MedlinePlus =
| MedlinePlus = a617008
| DailyMedID = Ribociclib
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X -->
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X -->
| pregnancy_AU_comment =
| pregnancy_AU_comment =
| pregnancy_US = <!-- A/B/C/D/X/N -->
| pregnancy_category=
| pregnancy_category=
| routes_of_administration = Oral
| routes_of_administration = [[Oral administration|By mouth]]
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| class =
⚫
| ATC_prefix = L01
| legal_AU_comment =
⚫
| ATC_suffix = EF02
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| 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=Search Page - Drug and Health Product Register | date=23 October 2014 }}</ref>
| legal_DE = <!-- Anlage I, II, III -->
| legal_DE = <!-- Anlage I, II, III -->
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ = <!-- Class A, B, C -->
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_US = Rx-only
| 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 = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_status =
| legal_status =

<!-- Pharmacokinetic data -->
<!-- Pharmacokinetic data -->
| bioavailability =
| bioavailability = Unknown
| protein_bound = ~70%
| protein_bound = ~70%
| metabolism = Liver ([[CYP3A4]])
| metabolism = Liver ([[CYP3A4]])
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| elimination_half-life = 32.0 (29.7–54.7) hrs
| elimination_half-life = 32.0 (29.7–54.7) hrs
| duration_of_action=
| duration_of_action=
| excretion = 69% feces, 32% urine
| excretion = 69% feces, 23% urine

<!-- Identifiers -->
<!-- Identifiers -->
| index2_label = as salt
| CAS_number = 1211441-98-3
| CAS_number = 1211441-98-3
⚫
| class =
| ATCvet =
⚫
| ATC_prefix = L01
⚫
| ATC_suffix = XE42
| PubChem = 44631912
| PubChem = 44631912
| DrugBank = DB11730
| DrugBank = DB11730
Line 43: Line 53:
| UNII = TK8ERE8P56
| UNII = TK8ERE8P56
| KEGG = D10883
| KEGG = D10883
⚫
| KEGG2 = D10979
| ChEMBL = 3545110
| ChEMBL = 3545110
| synonyms = LEE 011
| synonyms = LEE 011

<!-- Chemical and physical data -->
<!-- Chemical and physical data -->
⚫
| IUPAC_name = 7-Cyclopentyl-''N'',''N''-dimethyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}-7''H''-pyrrolo[2,3-d]pyrimidine-6-carboxamide
| chemical_formula =
| C=23 | H=30 | N=8 | O=1
| C=23 | H=30 | N=8 | O=1
| molecular_weight =
| smiles = CN(C)C(=O)c1cc2cnc(nc2n1C3CCCC3)Nc4ccc(cn4)N5CCNCC5
| 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)
| 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)
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}}
}}


'''Ribociclib''' (trade name '''Kisqali'''<ref name=kf/>) is an inhibitor of [[cyclin D1]]/[[CDK4]] and [[CDK6]], and is used for the treatment of certain kinds of [[breast cancer]].<ref name="Drugs.com">{{Drugs.com|pro|kisqali}} on Kisqali. Accessed 2017-09-08.</ref> It is also being studied as a treatment for other drug-resistant cancers.<ref name=Samson2014>{{cite journal |last1=Samson |first1=Kurt |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> It was developed by [[Novartis]] and [[Astex Pharmaceuticals]].<ref>{{cite news|url=https://www.novartis.com/news/media-releases/novartis-lee011-ribociclib-granted-fda-priority-review-first-line-treatment|title=Novartis LEE011 (ribociclib) granted FDA Priority Review for first-line treatment of HR+/HER2- advanced breast cancer|publisher=[[Novartis]]|date=2016-11-01}}</ref>
'''Ribociclib''', sold under the brand name '''Kisqali''', is a [[medication]] used for the treatment of certain kinds of [[breast cancer]].<ref name="Drugs.com">{{Drugs.com|pro|kisqali}} on Kisqali. Accessed 8 September 2017.</ref> Ribociclib is a [[kinase]] inhibitor.<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}}</ref><ref>{{Cite web|title=Kisqali (ribociclib) Treatment: HR+/HER2- mBC |url=https://www.hcp.novartis.com/products/kisqali/metastatic-breast-cancer/|access-date=24 August 2021|website=Novartis }}</ref> 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|title=Novartis LEE011 (ribociclib) granted FDA Priority Review for first-line treatment of HR+/HER2- advanced breast cancer|publisher=[[Novartis]]|date=1 November 2016}}</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 by the US [[Food and Drug Administration]] (FDA) 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> by the [[European Medicines Agency]] (EMA) 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}}</ref> and for use in the [[National Health Service]] (NHS) by [[National Institute for Health and Care Excellence]] (NICE) in February 2021.<ref name=":0" /><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==
==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" />
Ribociclib was approved by the [[US FDA]] in March 2017 and the [[European Medicines Agency]] in August 2017 for use in combination with an [[aromatase inhibitor]] to treat [[Hormone receptor|HR-positive]], [[HER2/neu|HER2-negative]] advanced or metastatic breast cancers.<ref name=kf>[http://www.genengnews.com/gen-news-highlights/fda-clears-novartis-kisqali-for-combination-breast-cancer-therapy/81254019 FDA Clears Novartis Kisqali for Combination Breast Cancer Therapy. March 2017]</ref><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=2017-08-31}}</ref>

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" />


==Side effects==
==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 diarrea (35% vs. 22%), as was [[alopecia]] (33% vs. 16%). The drug also [[QT prolongation|increases QT time]] and liver enzymes ([[alanine transaminase]], [[aspartate transaminase]]).<ref name="Drugs.com" /><ref name="EPAR" />
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 [[QT prolongation|increases the QT interval]] and liver enzymes ([[alanine transaminase]], [[aspartate transaminase]]).<ref name="Drugs.com" /><ref name="EPAR" />

The most common side effects include infections, low levels of white blood cells, headache, cough, nausea (feeling sick), 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==
== 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="Drugs.com" /><ref name="EPAR" />
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="Drugs.com" /><ref name="EPAR" />


Ribociclib itself is a moderate to strong CYP3A4 inhibitor and therefore can increase concentrations of other drugs that share this metabolism, as has been shown with [[midazolam]]. It also inhibits a number of [[transporter protein]]s and could thus theoretically interfere with the transport of other drugs. It could also amplify [[QT prolongation]] of other drugs such as [[antiarrhythmic]]s, clarithromycin, and [[haloperidol]].<ref name="Drugs.com" /><ref name="EPAR" />
Ribociclib itself is a moderate to strong CYP3A4 inhibitor and therefore can increase concentrations of other drugs that share this metabolism, as has been shown with [[midazolam]]. It also inhibits a number of [[transporter protein]]s 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 [[antiarrhythmic]]s, clarithromycin, and [[haloperidol]].<ref name="Drugs.com" /><ref name="EPAR" />


==Pharmacology==
==Pharmacology==
===Mechanism of action===
===Pharmacodynamics===
{{detail|CDK inhibitor}}
{{details|CDK inhibitor}}
[[Cyclin-dependent kinase]]s (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/><ref>{{cite journal |last1=Kim |first1=S. |last2=Loo |first2=A. |last3=Chopra |first3=R. |last4=Caponigro |first4=G. |last5=Huang |first5=A. |last6=Vora |first6=S. |last7=Parasuraman |first7=S. |last8=Howard |first8=S. |last9=Keen |first9=N. |last10=Sellers |first10=W. |last11=Brain |first11=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> This has led to the idea that [[CDK4 inhibitor|inhibiting CDK4]] will slow the growth of tumors by reactivating these tumor suppressors.
[[Cyclin-dependent kinase]]s (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 gene]]s.<ref name=Samson2014>{{cite journal |last1=Samson |first1=Kurt | name-list-style = vanc |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 | display-authors = 6 |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 [[Anaplastic lymphoma kinase|ALK]] or an [[Mitogen-activated protein kinase kinase|MEK]] inhibitor, ribociclib has been shown to have a synergistic effect, resulting in improved responses.<ref>{{cite journal |first1=Jeffrey Alan |last1=Sosman |first2=Muaiad |last2=Kittaneh |first3=Martijn P. J. K. |last3=Lolkema |first4=Michael Andrew |last4=Postow |first5=Gary |last5=Schwartz |first6=Catherine |last6=Franklin |first7=Alessandro |last7=Matano |first8=Suraj |last8=Bhansali |first9=Sudha |last9=Parasuraman |first10=Kevin |last10=Kim |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 |pages=9009 |url=http://hwmaint.meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/9009 }}</ref><ref>{{cite journal |last1=Wood |first1=Andrew C. |last2=Krytska |first2=Kateryna |last3=Ryles |first3=Hannah |last4=Sano |first4=Renata |last5=Li |first5=Nanxin |last6=King |first6=Frederick |last7=Smith |first7=Timothy |last8=Tuntland |first8=Tove |last9=Kim |first9=Sunkyu |last10=Caponigro |first10=Giordano |last11=He |first11=You Qun |last12=Jennifer |first12=Harris |last13=Mosse |first13=Yael |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 |pages=1000 |doi=10.1158/1538-7445.AM2014-1000 }}</ref> Again, this is likely a result of "[[crosstalk (biology)|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. It is also of interest that utilizing ribociclib in combination with other agents has been shown to reduce the development of resistance to these agents.<ref name=Samson2014/> In other words, cancer’s development of [[drug resistance]] can be mitigated with the addition of ribociclib to the therapeutic regime.
When used in combination with other drugs such as an [[ALK inhibitor|ALK]] 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 |display-authors=6 |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 |pages=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-status=dead }}</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 | display-authors = 6 |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 |pages=1000 |doi=10.1158/1538-7445.AM2014-1000 }}</ref> Again, this is likely a result of "[[crosstalk (biology)|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===
==Clinical trials==
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 protein]]s.<ref name="Drugs.com" /><ref name="EPAR" />
Ribociclib has been shown to be well-tolerated, although its best response as a single agent as of 2014 has been stable disease.<ref>{{cite journal |first1=B. |last1=Geoerger |first2=F. |last2=Bourdeaut |first3=S.G. |last3=Dubois |first4=M.D. |last4=Dewire |first5=A. |last5=Marabelle |first6=A.D. |last6=Pearson |first7=S. |last7=Modak |first8=R. |last8=Kan |first9=A. |last9=Matano |first10=S.G. |last10=Bhansali |first11=S. |last11=Parasuraman |first12=S.N. |last12=Chi |year=2014 |title=455P Phase I study of LEE011 (CDK4/6 inhibitor) in patients with malignant rhabdoid tumors, neuroblastoma, and cyclin D–CDK4/6 pathway-activated tumors |journal=Annals of Oncology |volume=25 |issue=suppl 4 |pages=iv151–2 |doi=10.1093/annonc/mdu331.15 |url=http://annonc.oxfordjournals.org/content/25/suppl_4/iv151.3.short }}</ref> In October 2016, good results (increased [[progression-free survival]]) were reported from the MONALEESA-2 trial (in combination with [[letrozole]]) in metastatic [[breast cancer]].<ref>[http://www.medpagetoday.com/hematologyoncology/BreastCancer/62304 Anti-CDK4/6 Boosts PFS in Metastatic Breast Cancer. Oct 2016]</ref>


The substance is mainly metabolized by CYP3A4 and subsequently by various [[Phase II metabolism|phase II enzymes]], resulting in a large number of metabolites. Those with highest blood plasma concentrations in humans are called CCI284 (an unspecified ''[[Nitrogen|N]]''-[[hydroxylation]] product), LEQ803 (the ''N''-[[demethylation]] product) and M1 (a [[glucuronide]]). All metabolites have negligible clinical activity.<ref name="Drugs.com" /><ref name="EPAR" />
{{as of|2017|09}}, ribociclib is in phase II development for several indications, including [[liposarcoma]],<ref>{{ClinicalTrialsGov|NCT03096912|A Study Assessing Efficacy & Safety of Ribociclib in Patients With Advanced Well/Dedifferentiated Liposarcoma}}</ref> [[endometrial carcinoma]]<ref>{{ClinicalTrialsGov|NCT03008408|Study of Ribociclib (LEE011), Everolimus, and Letrozole, in Patients With Advanced or Recurrent Endometrial Carcinoma}}</ref> and [[neuroendocrine tumors]] of the [[foregut]].<ref>{{ClinicalTrialsGov|NCT02420691|LEE011 in Neuroendocrine Tumors of Foregut Origin}}</ref>

Ribociclib has a slight tendency to [[Bioaccumulation|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="Drugs.com" /><ref name="EPAR" />


==Chemistry==
==Chemistry==
Ribociclib is used in form of its [[tartrate]] 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=2017-08-31}}</ref>
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}}</ref>

== History ==
Ribociclib is the only [[CDK4]]/[[CDK6]] inhibitor with a proven 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 press release |title=Novartis presents new Kisqali data showing longest median overall survival ever reported in HR+/HER2- advanced breast cancer|url=https://www.novartis.com/news/media-releases/novartis-presents-new-kisqali-data-showing-longest-median-overall-survival-ever-reported-hrher2-advanced-breast-cancer|access-date=19 October 2021|website=Novartis|language=en}}</ref>{{Unreliable medical source|date=October 2021}} The European Society of Medical Oncology (ESMO) assigned the highest score on the 'Magnitude of Clinical Benefit Scale' for Kisqali.<ref>{{Cite web|title=ESMO-Magnitude of Clinical Benefit Scale|url=https://www.esmo.org/guidelines/esmo-mcbs|access-date=19 October 2021|website=ESMO}}</ref>{{Failed verification|date=October 2021}}


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" /> The study is scheduled to run until September 2020.<ref>{{ClinicalTrialsGov|NCT01958021|Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer.(MONALEESA-2)}}</ref>
==See also==
*[[Palbociclib]], similar mechanism and indications


==References==
== References ==
{{reflist|35em}}
{{reflist}}


{{Chemotherapeutic agents}}
{{Chemotherapeutic agents}}
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[[Category:Protein kinase inhibitors]]
[[Category:Protein kinase inhibitors]]
[[Category:Carboxamides]]
[[Category:Carboxamides]]
[[Category:CYP3A4 inhibitors]]
[[Category:Pyridines]]
[[Category:Drugs developed by Novartis]]
[[Category:Pyrimidines]]
[[Category:1-Piperazinyl compounds]]
[[Category:Cyclopentanes]]
[[Category:CDK inhibitors]]

Latest revision as of 02:46, 31 March 2024

Ribociclib
Clinical data
Trade namesKisqali
Other namesLEE 011
AHFS/Drugs.comMonograph
MedlinePlusa617008
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityUnknown
Protein binding~70%
MetabolismLiver (CYP3A4)
Elimination half-life32.0 (29.7–54.7) hrs
Excretion69% feces, 23% urine
Identifiers
  • 7-Cyclopentyl-N,N-dimethyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.234.566 Edit this at Wikidata
Chemical and physical data
FormulaC23H30N8O
Molar mass434.548 g·mol−1
3D model (JSmol)
  • CN(C)C(=O)c1cc2cnc(nc2n1C3CCCC3)Nc4ccc(cn4)N5CCNCC5
  • InChI=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)
  • Key:RHXHGRAEPCAFML-UHFFFAOYSA-N

Ribociclib, sold under the brand name Kisqali, is a medication used for the treatment of certain kinds of breast cancer.[6] Ribociclib is a kinase inhibitor.[7][8] It was developed by Novartis and Astex Pharmaceuticals.[9]

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.[5]

Ribociclib was approved by the US Food and Drug Administration (FDA) in March 2017,[10][11] by the European Medicines Agency (EMA) in August 2017,[5][12] and for use in the National Health Service (NHS) by National Institute for Health and Care Excellence (NICE) in February 2021.[7][13]

Medical uses[edit]

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.[4][10]

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.[5] In pre‑ or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone‑releasing hormone (LHRH) agonist.[5]

Side effects[edit]

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).[6][12]

The most common side effects include infections, low levels of white blood cells, headache, cough, nausea (feeling sick), vomiting, diarrhoea, constipation, tiredness, hair loss and rash.[5] 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).[5]

Interactions[edit]

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.[6][12]

Ribociclib itself is a moderate to strong CYP3A4 inhibitor and therefore 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.[6][12]

Pharmacology[edit]

Pharmacodynamics[edit]

Further information: 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.[14][15]

When used in combination with other drugs such as an ALK or an MEK inhibitor, ribociclib has been shown to have a synergistic effect, resulting in improved responses.[16][17] 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.[14]

Pharmacokinetics[edit]

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.[6][12]

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.[6][12]

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.[6][12]

Chemistry[edit]

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.[18]

History[edit]

Ribociclib is the only CDK4/CDK6 inhibitor with a proven 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.[19][unreliable medical source?] The European Society of Medical Oncology (ESMO) assigned the highest score on the 'Magnitude of Clinical Benefit Scale' for Kisqali.[20][failed verification]

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.[12] The study is scheduled to run until September 2020.[21]

References[edit]

  1. ^ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  2. ^ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
  3. ^ "Search Page - Drug and Health Product Register". 23 October 2014.
  4. ^ a b "Kisqali- ribociclib tablet, film coated". DailyMed. 4 May 2023. Retrieved 9 July 2023.
  5. ^ a b c d e f g "Kisqali EPAR". European Medicines Agency (EMA). 31 March 2023. Retrieved 9 July 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ^ a b c d e f g FDA Professional Drug Information on Kisqali. Accessed 8 September 2017.
  7. ^ a b "Thousands of breast cancer patients to have routine access to NICE-approved drug combination". NICE (Press release). Retrieved 8 March 2021.
  8. ^ "Kisqali (ribociclib) Treatment: HR+/HER2- mBC". Novartis. Retrieved 24 August 2021.
  9. ^ "Novartis LEE011 (ribociclib) granted FDA Priority Review for first-line treatment of HR+/HER2- advanced breast cancer" (Press release). Novartis. 1 November 2016.
  10. ^ a b "Kisqali (ribociclib) Tablets". U.S. Food and Drug Administration (FDA). 28 March 2017. Retrieved 9 July 2023.
  11. ^ "FDA Clears Novartis Kisqali for Combination Breast Cancer Therapy". Genetic Engineering and Biotechnology News. 14 March 2017. Retrieved 9 July 2023.
  12. ^ a b c d e f g h "Kisqali: EPAR – Product Information" (PDF). European Medicines Agency. 31 August 2017.
  13. ^ "Life-extending drug for incurable breast cancer approved for NHS use". The Guardian. 26 February 2021. Retrieved 8 March 2021.
  14. ^ a b Samson K (2014). "LEE011 CDK Inhibitor Showing Early Promise in Drug-Resistant Cancers". Oncology Times. 36 (3): 39–40. doi:10.1097/01.COT.0000444043.33304.c1.
  15. ^ Kim S, Loo A, Chopra R, Caponigro G, Huang A, Vora S, et al. (2014). "Abstract PR02: LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6- Reactivating Rb in cancer". Molecular Cancer Therapeutics. 12 (11_Supplement): PR02. doi:10.1158/1535-7163.TARG-13-PR02.
  16. ^ Sosman JA, Kittaneh M, Lolkema MP, Postow MA, Schwartz G, Franklin C, et al. (2014). "A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: Early encouraging clinical activity". Journal of Clinical Oncology. 32 (15 Suppl): 9009. doi:10.1200/jco.2014.32.15_suppl.9009. Archived from the original on 7 October 2015. Retrieved 14 January 2017.
  17. ^ Wood AC, Krytska K, Ryles H, Sano R, Li N, King F, et al. (2014). "Abstract 1000: Combination CDK4/6 and ALK inhibition demonstrates on-target synergy against neuroblastoma". Cancer Research. 74 (19 Supplement): 1000. doi:10.1158/1538-7445.AM2014-1000.
  18. ^ "Kisqali: EPAR – Public assessment report" (PDF). European Medicines Agency. 31 August 2017.
  19. ^ "Novartis presents new Kisqali data showing longest median overall survival ever reported in HR+/HER2- advanced breast cancer". Novartis (Press release). Retrieved 19 October 2021.
  20. ^ "ESMO-Magnitude of Clinical Benefit Scale". ESMO. Retrieved 19 October 2021.
  21. ^ Clinical trial number NCT01958021 for "Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer.(MONALEESA-2)" at ClinicalTrials.gov
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