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Palbociclib is an orally available cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity. Palbociclib selectively inhibits cyclin-dependent kinase 4 (CDK4) and 6 (CDK6), thereby inhibiting retinoblastoma (Rb) protein phosphorylation early in the G1 phase leading to cell cycle arrest. This suppresses DNA replication and decreases tumor cell proliferation. CDK4 and 6 are serine/threonine kinases that are upregulated in many tumor cell types and play a key role in the regulation of cell cycle progression.
Palbociclib is a unique cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Palbociclib is associated with transient and usually mild elevations in serum aminotransferase during therapy but has yet to be linked to cases of clinically apparent acute liver injury.
Mechanism of Action of Palbociclib
Palbociclib is an oral, reversible, selective, small-molecule inhibitor of CDK4 and CDK6. CDK4 and CDK6 along with their regulatory partner cyclin D1 play a key role in regulating the G1- to S-phase cell-cycle transition via regulation of phosphorylation of the retinoblastoma (Rb) protein.
Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma protein (Rb) phosphorylation resulting in reduced E2F expression and signaling and increased growth arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens leads to increased cell senescence, which was sustained for up to 6 days following drug removal. In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling and tumor growth compared to each drug alone.
Palbociclib is an orally available cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity. Palbociclibselectively inhibits cyclin-dependent kinase 4 (CDK4) and 6 (CDK6), thereby inhibiting retinoblastoma (Rb) protein phosphorylation early in the G1 phase leading to cell cycle arrest. This suppresses DNA replication and decreases tumor cell proliferation. CDK4 and 6 are serine/threonine kinases that are upregulated in many tumor cell types and play a key role in the regulation of cell cycle progression.
Palbociclib Indications
- Palbociclib is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
- Palbociclib is approved to be used with other drugs to treat – Breast cancer that is hormone receptor positive(HR+) and HER2 negative(HER2-) and is advanced or has metastasized(spread to other parts of the body). It is used with fulvestrant in women whose disease has gotten worse after treatment with hormone therapy.
It is used with an aromatase inhibitor in postmenopausal women who have not been treated with hormone therapy.
Palbociclib is also being studied in the treatment of other types of cancer. - For HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women OR fulvestrant in women with disease progression following endocrine therapy.
- Breast Cancer
- Breast Cancer Metastatic
- Liposarcoma
- Advanced Breast Cancer
- Metastatic Breast Cancer
- Refractory, advanced Breast cancer
- Refractory, metastatic Breast cancer
FDA Label
- For the treatment of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor; in combination with fulvestrant in women who have received prior endocrine therapy.
- In pre- or perimenopausal women, endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.
- Palbociclib is a unique cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Palbociclib is associated with transient and usually mild elevations in serum aminotransferase during therapy but has yet to be linked to cases of clinically apparent acute liver injury.
Contraindications of Palbociclib
- Palbociclib is contraindicated in women having a pre-menopausal hormonal status, during pregnancy and lactation.
- High cholesterol
- Disorder of the Blood Vessels of the Brain
- Obstruction of a Blood Vessel by a Blood Clot
- Hardening of the Liver
- Severe liver disease
- Osteoporosis
- Decreased Calcification or Density of Bone
- 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
- Abnormal liver function tests
- Pregnancy
- A mother who is producing milk and breastfeeding
- Increased Cardiovascular Event Risk
- Allergies to Palbociclib
Dosage of Palbociclib
Strengths: 75 mg; 100 mg; 125 mg
Breast Cancer
- 28-day cycle: 125 mg orally once a day for 21 consecutive days followed by 7 days off
Side Effects of Palbociclib
The Most Common
- abdominal pain
- bone fractures
- increased blood pressure
- increased cholesterol levels
- signs of infection (e.g., severe fever, chills, mouth ulcers, shortness of breath, sudden lack of energy)
- signs of depression (such as feeling sad, losing interest in things you used to enjoy, weight changes, changes in sleep habits, feelings of guilt or worthlessness, thoughts of suicide)
- signs of high blood sugar (e.g., frequent urination, increased thirst, excessive eating, unexplained weight loss, poor wound healing, infections, fruity breath odor)
- signs of liver problems (e.g., yellow skin and eyes, nausea, loss of appetite, dark-colored urine)
- unusual vaginal bleeding
Less Common
- Bone fracture
- breast pain
- chest pain
- constipation
- diarrhea
- dizziness
- dry skin
- fatigue
- headache
- hot flushes
- increase or loss of appetite
- increased sweating
- joint stiffness
- chills, fever, or flu-like symptoms
- mental depression
- swelling of the feet or lower legs
Rare
- Continuing or severe nervousness
- cough
- dizziness or lightheadedness
- fainting
- fast heartbeat
- heart attack
- increased sweating
- nausea
- pain in the chest, groin, or legs, especially the calves
- severe and sudden, unexplained troubled breathing
- severe, sudden 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
- slurred speech
- sudden loss of coordination
- sudden, severe weakness or numbness in the arm or leg
Drug Interactions of Palbociclib
Palbociclib may interact with following drugs, supplements & may change the efficacy of drugs
- alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
- anti-cancer medications (e.g., cabazitaxel, docetaxel; doxorubicin; etoposide, ifosfamide, irinotecan, vincristine)
- antipsychotics (e.g., aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
- calcitriol
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- corticosteroids (e.g., budesonide, dexamethasone)
- cyclosporine
- domperidone
- estrogens (e.g., conjugated estrogen, estradiol, ethinyl estradiol)
- “gliptin” insulin is low or not working well. সহজ বাংলা: রক্তে চিনি বেশি থাকার রোগ।" data-rx-term="diabetes" data-rx-definition="Diabetes is a condition where blood sugar stays too high because insulin is low or not working well. সহজ বাংলা: রক্তে চিনি বেশি থাকার রোগ।">diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- grapefruit juice
- HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., delavirdine, efavirenz, etravirine, nevirapine)
- HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
- lidocaine
- losartan
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
- mifepristone
- mirtazapine
- modafinil
- narcotic pain relievers (e.g., codeine, fentanyl, morphine, oxycodone)
- phenobarbital
- St. John’s Wort
- seizure medications (e.g., carbamazepine, gabapentin, levetiracetam, phenytoin, topiramate)
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
- sildenafil
- “statin” anti-cholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
- tamoxifen
- tocilizumab
- tofacitinib
- tolterodine
- trazodone
- tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
- venlafaxine
Pregnancy Category
AU TGA Pregnancy category: D
US FDA Pregnancy category: N (Not assigned)
Pregnancy
This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately. If you are able to become pregnant, you should use effective birth control while you are taking this medication and for at least 21 days after stopping the medication.
Lactation
It is not known if palbociclib passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding. The safety and effectiveness of using this medication have not been established for children.
References
