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Abemaciclib is a unique cyclin-dependent kinase inhibitor that is used in combination with an antiestrogen in the treatment of postmenopausal women with metastatic breast cancer. Abemaciclibis associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to be a rare cause of clinically apparent liver injury.
Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathway, with potential antineoplastic activity. Abemaciclib specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of the serine/threonine kinases CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation.
Mechanism of Action of Abemaciclib
Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signaling 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 [A27281, A27282]. Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors [A27281]. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point [A27281]. This leads to increased expression of downstream signaling molecules and activation 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 the transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing [A27281]. 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 [A27281]. Unlike other CDK inhibitors such as [DB09073] and [DB11730], abemaciclib exhibits greater selectivity for CDK4 compared to CDK6 [A27282].
Indications of Abemaciclib
- 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.
- Indicated 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.
- Since September 2017 Abemaciclib is approved in the US for “adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones”.[rx]
- In studies that compared fulvestrant plus abemaciclib to fulvestrant plus placebo in breast cancer patients, progression-free survival under abemaciclib therapy was 16.4 months on average, as compared to 9.3 months under the placebo regimen.[rx]
- Advanced Breast Cancer
- Metastatic Breast Cancer (MBC)
- Verzenios is indicated for the treatment of women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or an in women who have received prior endocrine therapy.
- In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.
Contra-Indications of Abemaciclib
- Extreme loss of body water
- Decreased function of bone marrow
- Anemia
- Decreased blood platelets
- Decreased white blood cells
- Decreased neutrophils a type of white blood cell
- Stomach or intestinal ulcer
- Liver Problems
- Blockage of normal bile flow
- Acute infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।" data-rx-term="inflammation" data-rx-definition="Inflammation is the body’s response to injury, infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।">inflammation of the pancreas
- kidney disease with reduction in kidney function
- High amount of jaundice. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।" data-rx-term="bilirubin" data-rx-definition="Bilirubin is a yellow pigment that can build up in jaundice. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।">bilirubin in the blood
- Ascites
- Abnormal liver function tests
- Pregnancy
- Thiopurine S-methyltransferase deficiency
- Hepatosplenic T-cell lymphoma
Dosage of Abemaciclib
Strengths: 150 mg, 200 mg
Breast Cancer
- In combination with fulvestrant or an aromatase inhibitor: 150 mg orally twice a day
- As Monotherapy: 200 mg orally twice a day
- Duration of Therapy: Until disease progression or unacceptable toxicity
Side Effects of Abemaciclib
The most common
- bloating or swelling of the face, arms, hands, lower legs, or feet
- blood in the urine or stools
- chest pain
- confusion
- a cough
- decreased urination
- diarrhea
- difficulty breathing
- dizziness
- dry mouth
- fever
- hoarseness
- increased heart rate
- irregular heartbeat
- lightheadedness
- lower back or side pain
Common
- pain in the chest, groin, or legs, especially the calves
- painful or difficult urination
- pale skin
- pinpoint red spots on the skin
- rapid breathing
- Change in taste
- dry mouth
- loss of taste
- loss or thinning of hair
- swelling or infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।" data-rx-term="inflammation" data-rx-definition="Inflammation is the body’s response to injury, infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।">inflammation of the mouth
Rare
- the general feeling of discomfort or illness
- itching
- loss of appetite
- nausea
- numbness or tingling in the face, arms, or legs
- rapid, shallow breathing
- a severe pain in the head or upper neck. সহজ বাংলা: মাথাব্যথা।" data-rx-term="headache" data-rx-definition="Headache means pain in the head or upper neck. সহজ বাংলা: মাথাব্যথা।">headache
- skin rash
- stomach pain or tenderness
- swelling of the feet or lower legs
- thickening of bronchial secretions
- trouble speaking or walking
- vomiting
- yellow eyes or skin
Drug Interactions of Abemaciclib
Abemaciclib drugs may interact with following drugs, supplements& may change the drug efficacy
- Albendazole
- amphotericin B
- Alprazolam
- azathioprine
- ketoconazole
- clozapine
- denosumab
- aminophylline
- amoxicillin
- clarithromycin
- lansoprazole
- empagliflozin
- metformin (Synjardy, Synjardy XR)
- bupropion
- butabarbital
- butabarbital
- butalbital
- immunosuppressants (e.g., prednisone, dexamethasone, tacrolimus, cyclosporine)
- natalizumab
- pimecrolimus
- metformin/saxagliptin (Kombiglyze XR)
- metformin / sitagliptin (Janumet, Janumet XR)
- methotrexate (Rasuvo, Trexall, Otrexup, Methotrexate LPF Sodium, Xatmep, Rheumatrex Dose Pack, Folex PFS)
- olsalazine
- other cancer medications (e.g., cyclophosphamide, doxorubicin, etoposide)
- sulfamethoxazole
- sulfasalazine
- trastuzumab
- vemurafenib
- verapamil
- voriconazole
- trimethoprim
- vaccines (e.g., yellow fever, BCG, cholera, typhoid, varicella, meningococcal, diphtheria)
- warfarin
Pregnancy Category
US FDA pregnancy category: N (Not Assigned)
Pregnancy
Safety has not been established during pregnancy.
Lactation
Due to the potential for serious adverse reactions, breastfeeding is not recommended during treatment and for at least 3 weeks after the last dose.
References
