Ribociclib, an anticancer drug used in the treatment of hormone receptor-positive (HR-positive) and human epidermal growth factor receptor 2-negative (HER2-negative) advanced or metastatic breast cancer, was developed as a targeted therapy and approved for medical use in 2017. Its history is marked by its effectiveness in inhibiting cyclin-dependent kinases 4 and 6 (CDK4/6), which play an important role in regulating cell-cycle progression and cancer cell proliferation. Ribociclib is a selective CDK4/6 inhibitor that is commonly used in combination with endocrine therapy, such as letrozole or fulvestrant, to improve treatment outcomes in patients with advanced breast cancer.
BRAND NAMES
Kisqali – Main brand name of ribociclib, available as oral tablets.
Kisqali Femara Co-Pack – Combination pack containing ribociclib and letrozole for the treatment of HR-positive, HER2-negative advanced breast cancer.
MECHANISM OF ACTION
Ribociclib is a selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. It blocks the activity of CDK4 and CDK6, preventing phosphorylation of the retinoblastoma (Rb) protein. This stops the progression of the cell cycle from the G1 phase to the S phase, thereby inhibiting DNA synthesis and cancer cell proliferation. As a result, ribociclib slows tumour growth and helps control the progression of hormone receptor-positive, HER2-negative breast cancer.
PHARMACOKINETICS
Absorption
Ribociclib is administered orally and is rapidly absorbed from the gastrointestinal tract. It reaches peak plasma concentration (Tmax) approximately 1–4 hours after administration. Its absolute bioavailability is about 65%. Food does not significantly affect its absorption, so it can be taken with or without food.
Distribution
Ribociclib is widely distributed throughout the body and has a large apparent volume of distribution of approximately 1,090 L. It is moderately bound to plasma proteins (about 70%), allowing distribution into body tissues. It reaches tumour tissues, where it inhibits CDK4/6 activity and prevents cancer cell proliferation.
Metabolism
Ribociclib is extensively metabolized in the liver, primarily by the cytochrome P450 enzyme CYP3A4. It undergoes oxidation and other metabolic reactions to form several metabolites. Some metabolites retain pharmacological activity, while others are inactive. Drugs that inhibit or induce CYP3A4 can significantly affect ribociclib concentrations in the body.
Elimination
Ribociclib is eliminated mainly through feces and, to a lesser extent, through urine. It is excreted primarily as metabolites, with a small amount eliminated unchanged. Its terminal elimination half-life is approximately 32 hours. Elimination may be affected by liver or kidney impairment.
PHARMACODYNAMICS
Ribociclib is a selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that prevents cancer cell proliferation by blocking cell-cycle progression from the G1 phase to the S phase. It inhibits phosphorylation of the retinoblastoma (Rb) protein, resulting in cell-cycle arrest and suppression of tumour growth. It is mainly used in combination with endocrine therapy for the treatment of hormone receptor-positive (HR-positive) and HER2-negative advanced or metastatic breast cancer.
ADMINISTRATION
It can be taken with or without food and should be swallowed whole with water without crushing, chewing or splitting. It is generally used in combination with endocrine therapy such as letrozole or fulvestrant. Regular monitoring of blood counts, liver function and ECG is recommended during treatment.
DOSAGE AND STRENGTH
Ribociclib is available as oral tablets in strengths of 200 mg. The recommended starting dose for adults is 600 mg once daily (three 200 mg tablets) for 21 consecutive days, followed by 7 days off treatment, completing a 28-day cycle. When used in combination with an aromatase inhibitor or fulvestrant, the dosage may be adjusted according to the patient's response and tolerability. Dose reductions to 400 mg or 200 mg once daily may be required in case of adverse effects.
DRUG INTERACTIONS
Ribociclib interacts with several medications, mainly through the CYP3A4 enzyme system. Strong CYP3A4 inhibitors, such as ketoconazole and clarithromycin, may increase ribociclib levels and toxicity. CYP3A4 inducers, such as rifampicin and carbamazepine, may decrease its effectiveness. It may also increase the risk of QT interval prolongation when combined with certain antiarrhythmic drugs. Concomitant use with other medications that cause QT prolongation should be avoided or carefully monitored. Regular monitoring is recommended during treatment.
FOOD INTERACTIONS
Ribociclib can be taken with or without food, as food does not significantly affect its absorption. Grapefruit and grapefruit juice should be avoided because they may increase ribociclib levels in the blood and increase the risk of side effects. Patients should maintain a balanced diet and avoid herbal supplements that may interfere with drug metabolism, particularly St. John's wort.
CONTRAINDICATIONS
Ribociclib is contraindicated in patients with known hypersensitivity to ribociclib or any of its ingredients. It should be avoided in patients with congenital long QT syndrome, significant QT interval prolongation or severe electrolyte abnormalities. Caution is required in patients with severe liver impairment, heart rhythm disorders and those taking medications that prolong the QT interval or strongly inhibit CYP3A4. It is generally not recommended during pregnancy and breastfeeding due to potential harm to the fetus or infant.
SIDE EFFECTS
Neutropenia (decreased white blood cell count).
Nausea and vomiting.
Diarrhea.
Constipation.
Fatigue and weakness.
Headache.
Hair loss (alopecia).
Anemia.
OVER DOSAGE
Ribociclib may cause severe neutropenia, nausea, vomiting, diarrhea, liver toxicity and QT prolongation. Management includes discontinuation of the drug, ECG monitoring, blood tests and supportive treatment. There is no specific antidote.
TOXICITY
Ribociclib toxicity may cause bone marrow suppression, severe neutropenia, liver damage and QT interval prolongation. Regular monitoring of blood counts, liver function and ECG is essential to prevent serious complications.
