Palbociclib (Mechanism of Action)

In this article, we will discuss Palbociclib (Mechanism of Action). So, let’s get started.

Palbociclib (IBRANCE®) tablets for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a kinase inhibitor. The molecular formula for palbociclib is C24H29N702. The molecular weight is
447.54 daltons. The chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d] pyrimidin-7(8H)-one.

Palbociclib is a yellow to orange powder. At or below pH 4.palbociclib behaves as a high-solubility compound. Above pH 4, the solubility of the drug substance reduces significantly.

Inactive ingredients: Microcrystalline cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, succinic acid, HPMC 2910/hypromellose, titanium dioxide, triacetin, and FD&C Blue
#2/Indigo Carmine Aluminum Lake. In addition, the 75 mg and 125 mg tablets contain red iron oxide and the 100 mg tablets contain yellow iron oxide.

Mechanism of Action

Palbociclib is an inhibitor of eyelin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK 4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, 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. In vitro 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 und letrozole increased the inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared to each drug alone.

Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an anti-estrogen in vitro did not become senescent and resumed proliferation following palbociclib withdrawal.


Cardiac Electrophysiology

The effect of palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 77 patients with breast cancer. Palbociclib had no large effect on QTc (ie., >20 ms) at 125 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days.

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