Palbociclib is a kinase inhibitor indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (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.

Targeted Cancer Therapy

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 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.

Palbociclib capsules are taken orally with food in combination with an aromatase inhibitor or fulvestrant. Recommended starting dose: 125 mg once daily taken with food for 21 days followed by 7 days off treatment. Dosing interruption and/or dose reductions are recommended based on individual safety and tolerability.

Palbociclib is primarily metabolized by CYP3A and Sulfotransferase (SULT) enzyme SULT2A1. Palbociclib is atime-dependent inhibitor of CYP3A.Agents That May Increase Palbociclib Plasma Concentrations: Effect of CYP3A-Inhibitors: Coadministration of a strong CYP3A inhibitor (Itraconazole) increased the plasma exposure of Palbociclib in patients by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., Clarithromycin, Indinavir, Itraconazole, Ketoconazole, Lopinavir/Ritonavir, Nefazodone, Nelfinavir, Posaconazole, Ritonavir, Saquinavir, Telaprevir, Telithromycin, And Voriconazole). Avoid grapefruit or grapefruit juice during Palbociclib treatment. If coadministration of Palbociclib with a strong CYP3A inhibitor cannot be avoided, reduce the dose of Palbociclib.Agents That May Decrease Palbociclib Plasma Concentrations: Effect of CYP3A Inducers: Coadministration of a strong CYP3A Inducer (Rifampin) decreased the plasma exposure of Palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (E.G., Phenytoin, Rifampin, Carbamazepine, Enzalutamide, and St John’s Wort).Drugs That May Have Their Plasma Concentrations Altered By Palbociclib: Coadministration of Midazolam with multiple doses of Palbociclib increased the Midazolam plasma exposure by 61%, in patients, compared to administration of Midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., Alfentanil, Cyclosporine, Dihydroergotamine, Ergotamine, Everolimus, Fentanyl, Pimozide, Quinidine, Sirolimus, And Tacrolimus) may need to be reduced, as Palbociclib may increase its exposure.

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Common side effects of Palbociclib include: WBC decreased, Neutrophils decreased, Neutropenia, Platelets decreased, infections, AST increased, ALT increased, Leukopenia, Fatigue, Nausea, Hair loss, Inflammation of the mouth and lips, Diarrhea, Anemia, Rash, Weakness/lethargy, Vomiting, Thrombocytopenia, Dry skin, Fever.

Lactation: Advise not to breastfeed

Neutropenia: Neutropenia was the most frequently reported adverse reaction. Monitor complete blood counts prior to starting Palbociclib therapy and at the beginning of each cycle, as well as on day 15 of the first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop grade 3 or 4 neutropenia. Febrile neutropenia has been reported in 1.8% of patients exposed to Palbociclib. One death due to neutropenic sepsis was observed. Physicians should inform patients to promptly report any episodes of fever.Embryo-Fetal Toxicity: Palbociclib can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Palbociclib and for at least 3 weeks after the last dose.

There is no known antidote for Palbociclib. The treatment of overdose of Palbociclib should consist of general supportive measures.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Palbociclib is an inhibitor of Cyclin-dependent kinases (CDK) 4 and 6. cyclin D1 and CDK4/6 are downstream of signaling pathways that lead to cellular proliferation. Palbociclib reduced cellular proliferation of Estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into s phase of the cell cycle. Treatment of breast cancer cell lines with the combination of Palbociclib and antiestrogens leads to decreased retinoblastoma (RB) protein phosphorylation resulting in reduced E2F expression and signaling, and increased growth arrest compared to treatment with each drug alone. Treatment of ER-positive breast cancer cell lines with the combination of Palbociclib and antiestrogens led to increased cell senescence compared to each drug alone, which was sustained for up to 6 days following Palbociclib removal and was greater if antiestrogen treatment was continued. 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 can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.