Abemaciclib

Uses

Abemaciclib is a medication used to treat HR+ HER2- advanced or metastatic breast cancer.

• Indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.

• Inidicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

Abemaciclib is also used to associated treatment for these conditions: Advanced Breast Cancer, Metastatic Breast Cancer

How Abemaciclib works

Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and tumor formation in various cancers. G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway. Activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins, which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb .

Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors . However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point . This leads to increased expression of downstream signalling molecules and activity of protein kinases that promote the cell cycle progression and initiation of DNA replication. Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing .

Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells . Unlike other CDK inhibitors such as Palbociclib and Ribociclib, abemaciclib exhibits greater selectivity for CDK4 compared to CDK6 .

Toxicity

According to the bacterial reverse mutation (Ames) assay, abemaciclib and its active metbolites M2 and M20 did not display mutagenic properties. Abemaciclib was not clastogenic in vitro rat bone marrow micronucleus assay. Repeat-dose toxicity studies were performed to assess the effects of abemaciclib in testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs which exceed the recommeded therapeutic doses in humans. The findings included decreased organ weights, intratubular cellular debris, hypospermia, tubular distillation, atrophy and degeneration or necrosis .

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of abemaciclib.
• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of abemaciclib.
• Take at the same time every day.
• Take with or without food.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of abemaciclib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Inhibition of hepatic CYP450 3A4 may also contribute.

The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors.

According to the product labeling, abemaciclib systemic exposure (AUC) is predicted to increase by up to 16-fold when administered with the potent CYP450 3A4 inhibitor ketoconazole.

Itraconazole, another potent inhibitor, is predicted to increase the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.2-fold.

In cancer patients, administration of a single 50 mg dose of abemaciclib (one-third the approved recommended dose of 150 mg) with clarithromycin 500 mg twice daily increased the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.5-fold relative to abemaciclib administered alone.

The moderate CYP450 3A4 inhibitors, diltiazem and verapamil, are predicted to increase the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.4-fold and 1.6-fold, respectively.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased exposure to abemaciclib may increase adverse effects such as nausea, vomiting, diarrhea, stomatitis, venous thromboembolism, hepatotoxicity, anemia, neutropenia, and thrombocytopenia.

Food has modest effects on the pharmacokinetics of abemaciclib.

A high-fat, high-calorie meal (800 to 1000 calories; 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the Cmax and AUC of abemaciclib plus its active metabolites by 26% and 9%, respectively.

MANAGEMENT: Abemaciclib may be administered with or without food.

Patients should avoid consumption of grapefruit and grapefruit juice during treatment with abemaciclib.

Abemaciclib Drug Interaction

Moderate: palbociclibUnknown: paclitaxel protein-bound, charcoal, diphenhydramine, multivitamin with minerals, multivitamin with minerals, tadalafil, methylcellulose, sulfamethoxazole / trimethoprim, ubiquinone, prochlorperazine, copper gluconate, fulvestrant, sodium iodide, metoprolol, acetaminophen, bioflavonoids, levothyroxine, ascorbic acid, cholecalciferol

Abemaciclib Disease Interaction

Major: hepatic dysfunctionModerate: diarrhea, ILD, neutropenia, VTE, lung toxicity

Volume of Distribution

The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV) .

Elimination Route

The plasma concentration of the drug increases in a dose-proportional manner. Following a single oral dose administration of 200 mg abemaciclib, the mean peak plasma concentration (Cmax) of 158 ng/mL is reached after 6 hours. The median time to reach maximum plasma concentration (Tmax) ranges from 4-6 hours following an oral administration of abemaciclib over a range of 50–275 mg , but may range up to 24 hours . The absolute bioavailability of the drug is reported to be 45% .

Half Life

The mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV) .

Clearance

The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV) .

Elimination Route

Following a single oral dose of 150mg radiolabeled abemaciclib, approximately 81% of the total dose was recovered in feces while 3% of the dose was detected in urine. The majority of the drug is exceted as metabolites .

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