Ribociclib

Ribociclib is an antineoplastic agent belonging to the pharmacological class of CDK (Cyclin-Dependent Kinase) inhibitors.

The FDA approves Ribociclib for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early, advanced or metastatic breast cancer.

Ribociclib exhibits a 65.8% bioavailability and reaches peak plasma levels quickly, in 1-4 hours and distributes evenly across red blood cells and plasma, binding to plasma proteins to a degree of around 70%. Metabolism in Phase I and II conjugates is produced via hepatic metabolism, primarily by CYP3A4. Predominantly excreted (69%), with a minor renal route (23%).

The most common side effects of ribociclib include decreased white blood cell count, nausea, fatigue, diarrhoea, hair loss, vomiting, constipation, headache, and back pain.

Ribociclib is available as an oral tablet.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Ribociclib is an antineoplastic agent belonging to the pharmacological class of CDK (Cyclin-Dependent Kinase) inhibitors.

Under certain tissue types, inhibition of cyclin-dependent kinase 4 and 6 (CDK4/6) may offer protection against neoplastic processes. For example, research on knockout mice has shown that CDK4 is unnecessary for normal mammary tissue development. Still, it is essential for the formation of mammary tumours produced by Ras, indicating a possible therapeutic window for a less harmful course of therapy. Many preclinical models have demonstrated the dose-dependent anticancer efficacy of ribociclib, which has been described as a highly selective CDK4/6 inhibitor. It stopped tumour cells at the G1 checkpoint, preventing them from multiplying and so inhibiting the development of the tumour cells.

Ribociclib reaches peak plasma time within 1-4 hours after administration.

Ribociclib reaches peak plasma concentration within 1-4 hours after administration.

Ribociclib is available as an oral tablet.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, with or without meals.

Ribociclib is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with:

• An aromatase inhibitor (such as letrozole) is the initial endocrine-based treatment for men, women, or premenopausal patients.
• With fulvestrant as the initial endocrine-based therapy or, in the case of postmenopausal women or males, as the disease progresses.

Orally: Administer Ribociclib tablets orally daily once a day with water. Unless advised by a healthcare professional, tablets should not be crushed, chewed, or broken. Ribociclib and letrozole are best taken at the same time daily, preferably in the morning, with the option to take them with or without food. Broken or damaged tablets should not be ingested. If a dose is missed or vomited, no additional dose should be taken on that day, and the next dose should be taken at the regular scheduled time.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Ribociclib is available as an oral tablet.

Dose Adjustment in Adult Patients:

Breast Cancer

For 21 days, administer 600 mg once a day, preferably in the morning. After seven days off, the medication is stopped to complete a 28-day cycle. Continue until the disease worsens or the toxicity becomes unacceptable. A luteinizing hormone-releasing hormone (LHRH) agonist should also be administered to premenopausal and perimenopausal women. Depending on each person's safety or tolerability, a dose decrease, stoppage, or withdrawal may be necessary.

• Hypersensitivity to Ribociclib or any of its excipients.
• Pregnancy and lactation.

• Patients should be closely monitored for pulmonary symptoms indicating interstitial lung disease (ILD) or pneumonia. When a patient's respiratory symptoms become worse or new, interrupt them and evaluate them to rule out ILD or pneumonia. In situations when ILD/pneumonitis is severe or recurring, permanently stop using Ribociclib.
• Interval Prolongation: Before starting ribociclib, perform electrocardiograms (ECGs) and electrolyte monitoring. ECGs should be repeated as necessary during the first cycle and at the start of the second. For six cycles, or as directed by a physician, check electrolytes at the beginning of each cycle. Do not use ribociclib with potent CYP3A inhibitors or medications that extend the QT interval.
• Increased QT Prolongation: When Tamoxifen is Used Concurrently: Ribociclib should not be used with tamoxifen.
• Liver Function Tests (LFTs) should be monitored before starting Ribociclib due to Hepatobiliary Toxicity. For the first two cycles, LFTs were monitored every two weeks, at the beginning of each of the subsequent four cycles, and as directed by a physician.
• Before starting Ribociclib treatment for neutropenia, get a complete blood count (CBC). For the first two cycles, check the CBC every two weeks, then at the start of each of the subsequent four cycles, and as directed by a physician.
• Ribociclib may be hazardous to developing fetus. Inform patients of the possible danger to an unborn child and advise safe contraception while they are receiving treatment.

• Common Adverse Effects: Neutropenia, leukopenia, infections, fatigue, nausea, headache, and diarrhoea.
• Less Common Adverse Effects: QT interval prolongation, hepatobiliary toxicity (increased transaminase levels), and hematologic abnormalities.
• Rare Adverse Effects: Interstitial lung disease/pneumonitis, QT prolongation with tamoxifen use, and embryo-fetal toxicity.

• Drug-Drug Interactions: Tamoxifen, antiarrhythmics (amiodarone, disopyramide, quinidine, sotalol), and other recognized QT-prolonging drugs (such as ciprofloxacin, methadone, moxifloxacin, azithromycin, haloperidol, bepridil, pimozide) increase the risk of QT interval prolongation. Potent CYP3A4 inhibitors (e.g., clarithromycin, telithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nefazodone, nelfinavir, telaprevir, verapamil) may raise the plasma concentration of ribociclib. It might reduce the effectiveness and plasma concentration of CYP3A4 inducers (phenytoin, rifampicin, carbamazepine, etc.). May increase the levels of CYP3A4 substrates in the serum (e.g., tacrolimus, ergotamine, dihydroergotamine, alfuzosin, cisapride, quetiapine, simvastatin, alfentanil, fentanyl, ciclosporin, midazolam).
• Food Interaction: It could increase systemic exposure to ribociclib when grapefruits or grapefruit juice are consumed. This may cause St. John's wort to have a lower serum concentration.

• Pregnancy

• Nursing Mothers

• Pediatric Use

• Absorption: With a mean absolute bioavailability of 65.8%, ribociclib reaches maximal plasma concentration (Cmax) in 1 to 4 hours of administration. There is no impact of a high-fat meal on absorption.
• Distribution: Ribociclib binds to human plasma proteins (~70%) independently of concentration. It equally distributes between red blood cells and plasma, with an apparent volume of distribution at steady-state (Vss/F) of 1090 L.
• Metabolism: Phase II conjugations and oxidation are involved in hepatic metabolism, mainly carried out by CYP3A4. Exposure is influenced by the metabolites M13, M4, and M1. However, the parent drug is primarily responsible for therapeutic action.
• Elimination: The apparent oral clearance (CL/F) of Ribociclib is 25.5 L/hr, and its plasma effective half-life is 32.0 hours. Feces account for 69% of elimination, with kidneys contributing 23%. The medication is extensively metabolized; 17% of the substance remains unaltered in faeces and 12% in urine.

• Parati MC, Pedersini R, Perego G, Reduzzi R, Savio T, Cabiddu M, Borgonovo K, Ghilardi M, Luciani A, Petrelli F. Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection. Breast Cancer (Dove Med Press). 2022 Apr 12;14:101-111. doi: 10.2147/BCTT.S341857. PMID: 35440873; PMCID: PMC9013420.
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• Decker T, Lüdtke-Heckenkamp K, Melnichuk L, Hirmas N, Lübbe K, Zahn MO, Schmidt M, Denkert C, Lorenz R, Müller V, Zahm DM, Mundhenke C, Bauer S, Thill M, Seropian P, Filmann N, Loibl S. Anti-hormonal maintenance treatment with the CDK4/6 inhibitor ribociclib after 1st line chemotherapy in hormone receptor positive / HER2 negative metastatic breast cancer: A phase II trial (AMICA). Breast. 2023 Dec;72:103575. doi: 10.1016/j.breast.2023.08.007. Epub 2023 Sep 1. PMID: 37690320; PMCID: PMC10507224.
• Burris HA 3rd. Ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Expert Rev Anticancer Ther. 2018 Mar;18(3):201-213. doi: 10.1080/14737140.2018.1435275. Epub 2018 Feb 19. PMID: 29457921.

• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Kisqali® (ribociclib)
• https://www.ema.europa.eu/en/documents/product-information/kisqali-epar-product-information_en.pdf
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209092s004lbl.pdf
• https://www.ncbi.nlm.nih.gov/books/NBK548818/