Ribociclib

Last updated

Ribociclib
Ribociclib skeletal.svg
Ribociclib-from-xtal-3D-bs-17.png
Clinical data
Trade names Kisqali
Other namesLEE 011
AHFS/Drugs.com Monograph
MedlinePlus a617008
License data
Routes of
administration 		By mouth
Drug class Antineoplastic, CDK inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Unknown
Protein binding ~70%
Metabolism Liver (CYP3A4)
Elimination half-life 32.0 (29.7–54.7) hrs
Excretion 69% 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 InfoCard 100.234.566 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H30N8O
Molar mass 434.548 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. [4] Ribociclib is a kinase inhibitor. [4] It was developed by Novartis and Astex Pharmaceuticals. [6]

Contents

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 for medical use in the United States in March 2017, [7] [8] in the European Union in August 2017, [5] [9] and in the United Kingdom in February 2021. [10] [11]

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. [4] [7]

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]

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. [12] Additionally, the FDA approved the ribociclib and letrozole co-pack for the same indication. [12]

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. [5] [13] [14]

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). [4] [9]

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

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. [4] [9]

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. [4] [9]

Pharmacology

Pharmacodynamics

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. [15] [16]

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. [17] [18] 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. [15]

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. [4] [9]

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. [4] [9]

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. [4] [9]

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. [19]

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. [20] The European Society of Medical Oncology (ESMO) assigned the highest score on the 'Magnitude of Clinical Benefit Scale' for ribociclib. [21]

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. [9]

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. [22] The marketing authorization holder is Novartis Europharm Limited. [22] 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. [23]

Related Research Articles

<span class="mw-page-title-main">Aromatase inhibitor</span> Class of drugs

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exogenously. They may also be used for chemoprevention in women at high risk for breast cancer.

<span class="mw-page-title-main">Zoledronic acid</span> Chemical compound

Zoledronic acid, also known as zoledronate and sold under the brand name Zometa among others, by Novartis among others, is a medication used to treat a number of bone diseases. These include osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, Paget's disease of bone and Duchenne muscular dystrophy (DMD). It is given by injection into a vein.

<span class="mw-page-title-main">Exemestane</span> Breast cancer medication

Exemestane, sold under the brand name Aromasin among others, is a medication used to treat breast cancer. It is a member of the class of antiestrogens known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers have estrogen receptors (ERs), and are called ER-positive. They may also be called estrogen-responsive, hormonally-responsive, or hormone-receptor-positive. Aromatase is an enzyme that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.

Breast cancer management takes different approaches depending on physical and biological characteristics of the disease, as well as the age, over-all health and personal preferences of the patient. Treatment types can be classified into local therapy and systemic treatment. Local therapy is most efficacious in early stage breast cancer, while systemic therapy is generally justified in advanced and metastatic disease, or in diseases with specific phenotypes.

<span class="mw-page-title-main">Neratinib</span> Chemical compound

Neratinib (INN), sold under the brand name Nerlynx, is a tyrosine kinase inhibitor anti-cancer medication used for the treatment of breast cancer.

A CDK inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. While there are multiple cyclin/CDK complexes regulating the cell cycle, CDK inhibitors targeting CDK4/6 have been the most successful; four CDK4/6 inhibitors have been FDA approved. No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.

<span class="mw-page-title-main">Palbociclib</span> Medication for HR+ HER2− breast cancer

Palbociclib, sold under the brand name Ibrance among others, is a medication developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy.

<span class="mw-page-title-main">Sacituzumab govitecan</span> Antibody-drug conjugate

Sacituzumab govitecan, sold under the brand name Trodelvy by Gilead Sciences, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate used for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer.

Kathleen I. Pritchard, is the head of oncology at Sunnybrook Health Sciences Centre in Toronto, Canada, specializing in breast cancer therapies, and leading the clinical trials division of the centre. She has authored numerous studies on women's health, breast cancer, hormone replacement therapy, public health, and research methodology. According to Thomson Reuters, Pritchard was one of the most cited researchers in the world in 2014 and 2015.

<span class="mw-page-title-main">Abemaciclib</span> Anti-breast cancer medication

Abemaciclib, sold under the brand name Verzenio among others, is a medication for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6.

<span class="mw-page-title-main">Alpelisib</span> Chemical compound

Alpelisib, sold under the brand name Piqray among others, is a medication used to treat certain types of breast cancer. It is used together with fulvestrant. It is taken by mouth. It is marketed by Novartis.

<span class="mw-page-title-main">Elacestrant</span> Chemical compound

Elacestrant, sold under the brand name Orserdu, is a selective estrogen receptor degrader (SERD) used in the treatment of breast cancer. It is taken by mouth.

<span class="mw-page-title-main">Non steroidal aromatase inhibitors</span>

Non-Steroidal Aromatase Inhibitors (NSAIs) are one of two categories of aromatase inhibitors (AIs). AIs are divided into two categories, steroidal aromatase inhibitors and non-steroidal aromatase inhibitors that is based on their mechanism of action and structure. NSAIs are mainly used to treat breast cancer in women. NSAIs binding is a reversible process where NSAIs binds to the aromatase enzyme through non-covalent interactions. When aromatase inhibitors (AIs) are used to treat breast cancer the main target is the aromatase enzyme which is responsible for the high estrogen level.

<span class="mw-page-title-main">Trastuzumab deruxtecan</span> Medication

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Trastuzumab/hyaluronidase, sold under the brand name Herceptin SC among others, is a fixed-dose combination medication for the treatment of HER2-overexpressing breast cancer in adults. It is a combination of trastuzumab and hyaluronidase.

Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.

<span class="mw-page-title-main">Inavolisib</span> Chemical compound

Inavolisib, sold under the brand name Itovebi, is an anti-cancer medication used for the treatment of breast cancer. It is an inhibitor and degrader of mutant phosphatidylinositol 3-kinase (PI3K) alpha. The PI3K-mediated signalling pathway has shown to play an important role in the development of tumours as dysregulation is commonly associated with tumour growth and resistance to antineoplastic agents and radiotherapy.

<span class="mw-page-title-main">Capivasertib</span> Medication

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References

  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. ↑ "Regulatory Decision Summary for Kisqali". Health Canada . 2 March 2018. Retrieved 8 June 2024.
  4. 1 2 3 4 5 6 7 8 9 10 "Kisqali- ribociclib tablet, film coated". DailyMed. 4 May 2023. Retrieved 9 July 2023.
  5. 1 2 3 4 5 6 7 8 "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. ↑ "Novartis LEE011 (ribociclib) granted FDA Priority Review for first-line treatment of HR+/HER2- advanced breast cancer" (Press release). Novartis. 1 November 2016. Archived from the original on 25 September 2018. Retrieved 27 January 2017.
  7. 1 2 "Kisqali (ribociclib) Tablets". U.S. Food and Drug Administration (FDA). 28 March 2017. Retrieved 9 July 2023.
  8. ↑ "FDA Clears Novartis Kisqali for Combination Breast Cancer Therapy". Genetic Engineering and Biotechnology News. 14 March 2017. Retrieved 9 July 2023.
  9. 1 2 3 4 5 6 7 8 "Kisqali: EPAR – Product Information" (PDF). European Medicines Agency. 31 August 2017. Archived from the original (PDF) on 18 June 2018. Retrieved 8 September 2017.
  10. ↑ "Thousands of breast cancer patients to have routine access to NICE-approved drug combination". NICE (Press release). Archived from the original on 15 March 2021. Retrieved 8 March 2021.
  11. ↑ "Life-extending drug for incurable breast cancer approved for NHS use". The Guardian . 26 February 2021. Retrieved 8 March 2021.
  12. 1 2 "FDA approves ribociclib with an aromatase inhibitor and ribociclib and letrozole co-pack for early high-risk breast cancer". U.S. Food and Drug Administration (FDA). 17 September 2024. Retrieved 15 October 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  13. ↑ "Kisqali - opinion on variation to marketing authorisation". European Medicines Agency (EMA). 17 October 2024. Retrieved 27 November 2024.
  14. ↑ "Novartis Kisqali receives European Commission approval in a broad population of patients with HR+/HER2- early breast cancer at high risk of recurrence". Novartis (Press release). Retrieved 27 November 2024.
  15. 1 2 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ "Kisqali: EPAR – Public assessment report" (PDF). European Medicines Agency. 31 August 2017. Archived from the original (PDF) on 18 June 2018. Retrieved 8 September 2017.
  20. ↑ Slamon DJ, Fasching PA, Hurvitz S, Chia S, Crown J, Martín M, et al. (May 2023). "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". Therapeutic Advances in Medical Oncology. 15: 17588359231178125. doi:10.1177/17588359231178125. PMC   10233570 . PMID   37275963.
  21. ↑ "ESMO-Magnitude of Clinical Benefit Scale". ESMO. Retrieved 19 October 2021.
  22. 1 2 "Kisqali - opinion on variation to marketing authorisation". European Medicines Agency (EMA). 18 October 2024. Retrieved 22 October 2024.
  23. ↑ "Novartis Kisqali® receives European Commission approval in a broad population of patients with HR+/HER2- early breast cancer at high risk of recurrence". The Manila Times. 27 November 2024. Retrieved 27 November 2024.
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