Palbociclib is a selective inhibitor of the cyclin-dependent kinases CDK4/6.
In the G1 phase of the cell cycle, mammalian cells must pass a checkpoint in order to complete the cell cycle and divide. CDK4/6 complex with cyclin D1 drive the phosphorylation of the retinoblastoma protein, Rb, which allows the cell to pass this checkpoint and commit to division. Regulation of one or more proteins involved in this checkpoint is lost in many cancers. However by inhibiting CDK4/6, palbociclib ensures that the cyclin D1-CDK4/6 complex cannot aid in phosphorylating Rb. This prevents the cell from passing the checkpoint and exiting G1, and in turn from proceeding through the cell cycle
Absorption: The mean Cmax of palbociclib is generally observed between 6 to 12 hours (time to reach maximum concentration, Tmax) following oral administration. The mean absolute bioavailability of Palbociclib after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5 to 4.2).
Distribution: Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The geometric mean apparent volume of distribution (Vz/F) was 2583 L (26% CV).
Elimination: The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the mean (± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of [14C]palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the material was excreted as metabolites