Abemaciclib

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

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

When administered orally, Abemaciclib is absorbed from the GIT and undergoes hepatic metabolism primarily by CYP3A4, generating active metabolites. It is sebsequently eliminated vai fecal (81%) and urinary (3%) with an 18.3-hour half-life.

The most common side effects of abemaciclib include hair loss, headache, cough, joint pain, dizziness, fatigue, and weight loss.

Abemaciclib 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.

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

Cyclin-dependent kinases 4 and 6 (also known as CDK4 and CDK6) are inhibited by Abemaciclib. When these kinases bind to D-cyclins, they become active. Cyclin D1 and CDK4/6 stimulate the phosphorylation of the retinoblastoma protein (Rb), the progression of the cell cycle, and the proliferation of estrogen receptor-positive (ER+) breast cancer cell lines. In vitro, persistent exposure to abemaciclib prevented the cell cycle's passage from G1 to S phase, which stopped Rb phosphorylation and caused senescence and apoptosis. Tumour size was decreased in breast cancer xenograft models when abemaciclib was administered daily, continuously, either alone or in conjunction with antiestrogens.

After a single 200-mg dose, Abemaciclib reaches its peak plasma time in approximately 8 hours.

A high-fat, high-calorie meal increases abemaciclib and metabolites' AUC by 9% and peak plasma concentration by 26%.

Abemaciclib 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 twice daily, with or without meals.

Abemaciclib is indicated for the following conditions:

• Combine with endocrine therapy (tamoxifen or aromatase inhibitor) as an adjuvant treatment for high-risk, node-positive, early-stage breast cancer that is hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative.
• As a single treatment for individuals with metastatic or advanced HR-positive, HER2-negative breast cancer who are still undergoing chemotherapy after receiving endocrine therapy.
• For HR-positive, HER2-negative advanced or metastatic breast cancer, use in combination with an aromatase inhibitor as the first endocrine-based therapy.
• In adults with advanced or metastatic HER2-negative, HR-positive breast cancer who are facing the progression of their disease after endocrine therapy, prescribe in addition to fulvestrant.

Orally: Patients take Abemaciclib orally, using tablets swallowed with water once daily. Patients should refrain from crushing, chewing, or breaking the tablets unless instructed by their healthcare provider. Adherence to these instructions is crucial for the medication to work optimally in managing the specified conditions, emphasizing the importance of following the healthcare professional's guidance for proper administration. Only take it if the tablet is fixed. Take the next dose at the scheduled time in case of a missed dose or vomiting.

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

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

Abemaciclib is available as an oral tablet.

Dose Adjustment in Adult Patients:

Early Breast Cancer

150 mg PO BID in addition to an aromatase inhibitor or tamoxifen.

Continue for a full two years or until a disease recurs or the toxicity becomes intolerable.

Advanced or Metastatic Breast Cancer

Monotherapy: 200 mg PO BID

Continue until the disease worsens or the toxicity becomes intolerable.

Combination:

150 mg orally BID plus an aromatase inhibitors.

Continue until the disease worsens or the toxicity becomes unacceptable.

Combination therapy with fulvestrant

150 mg PO BID PLUS

Combination treatment on Days 1, 15, and 29 with fulvestrant 500 mg IM PLUS 150 mg PO BID, and then once a month after that

Continue until the disease worsens or the toxicity becomes intolerable.

Considerations for Dosing

Men and women who are perimenopausal or premenopausal

Combination treatment utilizing fulvestrant or an aromatase inhibitor: Apply a gonadotropin-releasing hormone agonist (GnRH) treatment according to accepted clinical practice guidelines.

Avoid consuming grapefruit or its juice while taking Abemaciclib to avoid possible issues with drug metabolism. To control weight, eat a balanced diet and get regular exercise. Avoid drinking and smoking. Include leafy greens, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, broccoli, cauliflower, cabbage, beans, herbs, and spices. Avoid processed meats, fast food, fried foods, refined carbohydrates, and added sugar.

The dietary restriction should be individualized as per patient requirements.

• Diarrhoea: Abemaciclib may induce severe diarrhoea, leading to dehydration and infection. Patients should promptly initiate antidiarrheal therapy, increase oral fluids, and inform their healthcare provider at the first sign of loose stools.
• Neutropenia: Monitor complete blood counts regularly, including before initiating Abemaciclib therapy, every 2 weeks for the first 2 months, monthly for the following 2 months, and as clinically indicated.
• Interstitial Lung Disease (ILD)/Pneumonitis: Severe and fatal cases of ILD/pneumonitis have been reported. Carefully monitor for clinical symptoms or radiological changes suggestive of ILD/pneumonitis. Permanently discontinue Abemaciclib for Grade 3 or 4 ILD or pneumonitis.
• Hepatotoxicity: Elevated serum transaminase levels may occur. Conduct liver function tests (LFTs) before starting abemaciclib, with monitoring every two weeks for the first two months, monthly for the subsequent 2 months, and as clinically needed.
• Venous Thromboembolism: Monitor patients for signs of thrombosis and pulmonary embolism. Administer appropriate medical treatment if thrombotic events occur.
• Embryo-Fetal Toxicity: Abemaciclib poses a risk of fetal harm. Advise patients about potential fetal dangers and the necessity for effective contraception during treatment.

The adverse reactions related to Abemaciclib can be categorized as:

• Common Adverse Effects: Diarrhea, fatigue, nausea, abdominal pain, infections, anaemia, leukopenia, and decreased appetite.
• Less Common Adverse Effects: Elevated liver enzymes, vomiting, asthenia, headache, and thrombocytopenia.
• Rare Adverse Effects: Interstitial lung disease, venous thromboembolism, neutropenia, and gastrointestinal perforations.

Postmarketing Reports

Interstitial lung disease (ILD)/pneumonitis

The clinically relevant drug interactions of Abemaciclib are briefly summarized here.

Drug-Drug Interactions: Increased plasma concentrations with potent CYP3A4 inhibitors (e.g. clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole, voriconazole). Reduced plasma concentrations using a potent CYP3A4 inducer (such as rifampicin, phenytoin, or carbamazepine).

Food Interaction: St. John's wort reduced plasma concentrations. Higher plasma concentrations when grapefruit is consumed.

The common side effects of abemaciclib include

Nausea

Vomiting

Tiredness

Abdominal pain

Decreased appetite

Headache

Hair loss

Abnormal blood cell count

Cough

Joint pain

Dizziness

Stomatitis (Inflammation of the mouth)

Weight loss

Infection

• Pregnancy

There is no human data available to inform the risk associated with drugs.

Considering the mechanism of action and results from animal studies, this medication has the potential to harm a fetus when given to a pregnant woman. Pregnant women should be advised of this risk.

Based on AUC at the highest recommended human dose, the administration of abemaciclib during organogenesis was found to be teratogenic in animal data, resulting in decreased fetal weight at maternal exposures comparable to clinical exposure in humans.

Before starting treatment, observe if any females who are capable of becoming pregnant.

Encourage women who are capable of having children to use reliable contraception both during their treatment and for a minimum of three weeks following the last dosage.

Abemaciclib may reduce fertility in males who are capable of reproducing, according to research on animals.

• Nursing Mothers

If it is present in human breast milk, it is unknown.

Breastfeeding mothers should not breastfeed while taking abemaciclib and for at least three weeks following the last dose due to the possibility of severe adverse reactions in breastfed infants.

• Pediatric Use

The safety and effectiveness of Abemaciclib in pediatric patients have not been established.

Dose Adjustment in Kidney Impairment Patients:

Moderate to mild (CrCl 30-89 mL/min): No dosage alteration is necessary.

Not studied for severe, ESRD, or dialysis

Dose Adjustment in Hepatic Impairment Patients:

Moderate to mild (Child-Pugh A or B):

Very Serious (Child-Pugh C): Limit the number of doses to one per day.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Abemaciclib.

Signs and Symptoms

Overconsumption of Abemaciclib could lead to fatigue and diarrhoea.

Management

There is no specific antidote for Abemaciclib, and treatment should focus on managing adverse reactions.When an overdose occurs, stop the Abemaciclib immediately and start treating the patient with supportive and symptomatic care.

Pharmacodynamic

Patients with HR-positive and HER2-negative breast cancer who took fulvestrant in combination with it had a progression-free survival of 16.4 months, while those who took a placebo with fulvestrant had a progression-free survival of 9.3 months. For a median of 8.6 months following treatment 5, 19.7% of patients receiving abemaciclib as a monotherapy saw full or partial shrinkage of their tumours. In human tumor xenograft models, bemaciclib induces cell cycle arrest and exhibits antitumor activity.

It has not been demonstrated that abemaciclib causes clinically meaningful alterations in the QTc interval in patient studies or a healthy volunteer study.

Pharmacokinetics

• Absorption: Following a single oral dose of abemaciclib, it absorbs from the GIT and has a 45% bioavailability.
• Distribution: The drug exhibits a high plasma protein binding of about 96%, with a volume of distribution of about 690.3 L.
• Metabolism: N-desethylabemaciclib (M2), hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1) are among the active metabolites that are primarily formed in the liver by CYP3A4.
• Excretion: Approximately 3% of the drug and its metabolites are expelled through urine, and 81% are removed through faeces. The elimination half-life of bemaciclib is 18.3 hours.

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• Johnston S, O'Shaughnessy J, Martin M, Huober J, Toi M, Sohn J, André VAM, Martin HR, Hardebeck MC, Goetz MP. Abemaciclib as initial therapy for advanced breast cancer: MONARCH 3 updated results in prognostic subgroups. NPJ Breast Cancer. 2021 Jun 22;7(1):80. doi: 10.1038/s41523-021-00289-7. PMID: 34158513; PMCID: PMC8219718.
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• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Verzenio™ (abemaciclib)
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208716s006s007s008lbl.pdf
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