|Other names||LEE 011|
|Main uses||Breast cancer|
|Side effects||Low neutrophils, nausea, tiredness, diarrhea, hair loss, headache, rash, cough|
|By mouth (tablets)|
|Elimination half-life||32.0 (29.7–54.7) hrs|
|Excretion||69% feces, 23% urine|
|Chemical and physical data|
|Molar mass||434.548 g·mol−1|
|3D model (JSmol)|
Ribociclib, sold under the brand name Kisqali, is a medication used to treat certain kinds of breast cancer. Specifically it is used for HR-positive, HER2-negative disease. It is taken by mouth.
Common side effects include low neutrophils, nausea, tiredness, diarrhea, hair loss, headache, rash, and cough. Other side effects may include low phosphate, QT prolongation, and liver problems. Use in pregnancy may harm the baby. It works by blocking the enzymes CDK4 and CDK6.
Ribociclib was approved for medical use in Europe and the United States in 2017. In the United States it costs about 13,800 USD per 4 weeks as of 2021. This amount in the United Kingdom costs the NHS about £2,950.
Ribociclib was approved by the U.S. Food and Drug Administration (FDA) in March 2017. It was approved by the European Medicines Agency (EMA) in August 2017. It was approved for use in the NHS by NICE in February 2021. It can be used in combination with an aromatase inhibitor (such as letrozole) to treat HR-positive, HER2-negative advanced or metastatic breast cancers.
In the clinical trial relevant for the drug's approval, ribociclib significantly improved progression-free survival (PFS), that is, the time span the cancer did not get worse. For patients receiving placebo plus letrozole, PFS was 16 months on average, while under ribociclib plus letrozole, PFS was 25 months as of the January 2017 analysis. The study is scheduled to run until September 2020.
It is generally taken at a dose of 600 mg per day for 21 days followed by 7 days without medication.
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).
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.
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.
Mechanism of action
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.
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. 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. In other words, cancer's development of drug resistance can be mitigated with the addition of ribociclib to the therapeutic regime.
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 are bound to plasma proteins.
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.
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.
It is also being studied as a treatment for other drug-resistant cancers.
- Palbociclib, a drug with similar mechanism and indications
- "Ribociclib Monograph for Professionals". Drugs.com. Retrieved 17 October 2021.
- "DailyMed - KISQALI- ribociclib tablet, film coated". dailymed.nlm.nih.gov. Retrieved 17 October 2021.
- "Kisqali". Retrieved 17 October 2021.
- BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1055. ISBN 978-0-85711-369-6.CS1 maint: date format (link)
- "Ribociclib Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 17 October 2021.
- FDA Clears Novartis Kisqali for Combination Breast Cancer Therapy. March 2017
- "Kisqali: EPAR – Product Information" (PDF). European Medicines Agency. 2017-08-31.
- "Thousands of breast cancer patients to have routine access to NICE-approved drug combination | News and features | News". NICE. Retrieved 2021-03-08.
- "Life-extending drug for incurable breast cancer approved for NHS use". the Guardian. 2021-02-26. Retrieved 2021-03-08.
- "Ribociclib (Kisqali) | Cancer information | Cancer Research UK". www.cancerresearchuk.org. Retrieved 2021-03-08.
- Clinical trial number NCT01958021 for "Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer.(MONALEESA-2)" at ClinicalTrials.gov
- FDA Professional Drug Information on Kisqali. Accessed 2017-09-08.
- 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.
- 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.
- 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.
- 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.
- "Kisqali: EPAR – Public assessment report" (PDF). European Medicines Agency. 2017-08-31.
- "Novartis LEE011 (ribociclib) granted FDA Priority Review for first-line treatment of HR+/HER2- advanced breast cancer". Novartis. 2016-11-01.
- Clinical trial number NCT03096912 for "A Study Assessing Efficacy & Safety of Ribociclib in Patients With Advanced Well/Dedifferentiated Liposarcoma" at ClinicalTrials.gov
- Clinical trial number NCT03008408 for "Study of Ribociclib (LEE011), Everolimus, and Letrozole, in Patients With Advanced or Recurrent Endometrial Carcinoma" at ClinicalTrials.gov
- Clinical trial number NCT02420691 for "LEE011 in Neuroendocrine Tumors of Foregut Origin" at ClinicalTrials.gov
- "Ribociclib succinate". Drug Information Portal. U.S. National Library of Medicine.