Drug information of Abemaciclib

Abemaciclib


Abemaciclib is used to treat advanced hormone-related breast cancer. Abemaciclib is used for this condition only if your tumor tests negative for a protein called human epidermal growth factor receptor 2.

Mechanism of effect

Inhibits cyclin-dependent kinases (CDKs) 4 and 6.

These kinases are activated upon binding to D cyclins and play a crucial role in signaling pathways, which lead to cell cycle progression and cellular proliferation.

In ER-positive breast cancer cells, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

Pharmacodynamic

Abemaciclib induces cell cycle arrest and exerts an antitumor activity in human tumor xenograft models 

Pharmacokinetics

-Bioavailability: 45% (single 200-mg dose)

-Peak plasma time: 8 hr (single 200-mg dose)

-Increase of AUC of abemaciclib and metabolites (9%) and peak plasma concentration (26%) with high-fat, high-calorie meal

 

-Protein bound: 96.3% (abemaciclib); M2 (93.4%); M18 (96.8%); M20 (97.8%)

-Vd: 690.3 L

-Half-Life Elimination:18.3 hours

-Metabolism:Abemaciclib is hepatically metabolized by CYP3A4 to several metabolites (N-desethylabemaciclib [M2], hydroxyabemaciclib [M20], hydroxy-N-desethylabemaciclib [M18], and an oxidative metabolite [M1])

M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma

-Elimination:Excretion, single 150-mg dose: Feces (81%); urine (~3%)

-Majority of the dose eliminated in feces was metabolites

Drug indications

Breast cancer

Breast Cancer

Dosage

Indicated for HR+/HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy as either monotherapy or in combination with fulvestrant

Also, indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with HR+/HER2- advanced or metastatic breast cancer

Monotherapy

  • 200 mg PO BID
  • Continue until disease progression or unacceptable toxicity

Combination therapy

  • With aromatase inhibitor
    • Abemaciclib: 150 mg PO BID PLUS
    • Continue until disease progression or unacceptable toxicity
  • With fulvestrant
    • Abemaciclib: 150 mg PO BID PLUS
    • Fulvestrant: 500 mg IM on Days 1, 15, and 29, and then once monthly thereafter
    • Continue until disease progression or unacceptable toxicity

Dosing: Adjustment for Toxicity

-Recommended abemaciclib dosage adjustments for adverse reactions:

Starting dose 200 mg twice a day (monotherapy):

First dose reduction: Reduce abemaciclib dose to 150 mg twice daily.

Second dose reduction: Reduce abemaciclib dose to 100 mg twice daily.

Third dose reduction: Reduce abemaciclib dose to 50 mg twice daily.

-Starting dose 150 mg twice a day (in combination with an aromatase inhibitor or fulvestrant):

First dose reduction: Reduce abemaciclib dose to 100 mg twice daily.

Second dose reduction: Reduce abemaciclib dose to 50 mg twice daily.

If unable to tolerate 50 mg twice daily: Discontinue abemaciclib treatment.

 

Hematologic toxicities:

Note: If blood cell growth factors are required, withhold abemaciclib dose for at least 48 hours after the last growth factor dose and until toxicity resolves to ≤ grade 2; resume abemaciclib at the next lower dose (unless already reduced due to the toxicity that required the growth factor).

Grade 1 or 2: No abemaciclib dosage adjustment necessary.

Grade 3: Withhold abemaciclib until toxicity resolves to ≤ grade 2 (no abemaciclib dosage reduction is necessary)

Grade 4 or recurrent grade 3: Withhold abemaciclib until toxicity resolves to ≤ grade 2 and then resume abemaciclib at the next lower dose.

 

Nonhematologic toxicities:

Diarrhea: At the first sign of loose stools, begin management with antidiarrheal agents and increase oral fluid intake.

Grade 1: No abemaciclib dosage adjustment necessary.

Grade 2: If toxicity does not resolve to ≤ grade 1 within 24 hours, withhold abemaciclib until resolution (no abemaciclib dosage reduction is necessary).

Grade 2 that persists or recurs after resumption at the same dose (despite maximal supportive measures): Withhold abemaciclib until toxicity resolves to ≤ grade 1 and then resume abemaciclib at the next lower dose.

Grade 3 or 4 or requires hospitalization: Withhold abemaciclib until toxicity resolves to ≤ grade 1 and then resume abemaciclib at the next lower dose.

 

Interstitial lung disease/pneumonitis:

Grade 1 or 2: No abemaciclib dosage adjustment necessary.

Persistent or recurrent grade 2 toxicity that does not resolve to baseline or grade 1 within 7 days (despite maximal supportive measures): Withhold abemaciclib until toxicity resolves to baseline or to ≤ grade 1 and then resume abemaciclib at the next lower dose.

Grade 3 or 4: Discontinue abemaciclib.

Other toxicities (excluding diarrhea, hematologic, hepatotoxicity, and interstitial lung disease/pneumonitis):

Grade 1 or 2: No abemaciclib dosage adjustment necessary.

Persistent or recurrent grade 2 toxicity that does not resolve to baseline or grade 1 within 7 days (despite maximal supportive measures): Withhold abemaciclib until toxicity resolves to baseline or to ≤ grade 1 and then resume abemaciclib at the next lower dose.

Grade 3 or 4: Withhold abemaciclib until toxicity resolves to baseline or to ≤ grade 1 and then resume abemaciclib at the next lower dose.

Drug contraindications

None

Side effects

anemia , Infection , Diarrhea , Headache , weight decrease , nausea , dry mouth , abdominal pain , vomiting , Cough , fever , pneumonia , tiredness , Leukopenia , vertigo

Fatigue , headache , dizziness ,Alopecia ,Weight loss ,Diarrhea ,nausea , decreased appetite , abdominal pain , vomiting , constipation , stomatitis ,xerostomia , dysgeusia ,Anemia ,lymphocytopenia , neutropenia , thrombocytopenia ,leukopenia ,Increased serum alanine aminotransferase , increased serum aspartate aminotransferase ,Infection ,Arthralgia ,Increased serum creatinine , Cough , Fever ,Dehydration ,Interstitial pulmonary disease , pneumonitis

dengue vaccine-elvitegravir/cobicistat/emtricitabine/tenofovir 

Alerts

-May cause fetal harm; advise women of reproductive potential to use effective contraception .

-Severe, life-threatening, or fatal ILD and/or pneumonitis can occur;

-In clinical trials, venous thromboembolic events (VTE) reported in patients treated with abemaciclib plus an aromatase inhibitor (5%) and in patients treated with abemaciclib plus fulvestrant (5%).

-Increased transaminases were observed in clinical trials.

-Neutropenia observed in clinical trials;

-Episodes of diarrhea have been associated with dehydration and infection; diarrhea incidence was greatest during the first month of dosing

-Abemaciclib is metabolized to several metabolites primarily by CYP3A4. Strong CYP3A4 inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity

Points of recommendation

-monitor for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea

-Monitor for signs and symptoms of venous thrombosis and pulmonary embolism and appropriately treat.

Pregnancy level

Forbidden

There are no available human data informing the drug-associated risk

Based on findings from animal studies and the mechanism of action, can cause fetal harm when administered to a pregnant woman

In animal data, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose

Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment

Advise females of reproductive potential to use effective contraception during treatment and for at least 3 weeks after the last dose

Based on findings in animals, abemaciclib may impair fertility in males of reproductive potential

Breast feeding warning

Unknown if distributed in human breast milk

Because of the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed while taking abemaciclib and for at least 3 weeks after the last dose

Related drugs

Ribociclib , Palbociclib

Drug forms

Verzenio

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