Pharmacokinetics
Pharmacokinetic studies of palbociclib after an oral dosage were performed on days 1, 2, 3, 21, and 22 of course 1. On day 2 of course 1 the palbociclib dose was held. On day 1 of course 1, palbociclib single dose serial blood samples were drawn pre-dose and 0.5, 1, 2, 4, 8 (±1), 24 (±4), and 48 (±4) hours (immediately prior to the Day 3 dose) after the oral dose. On day 21 of course 1, palbociclib steady state serial blood samples were collected pre-dose and 1, 2, 4, 8 (±1), and 24 (±4) hours (immediately prior to the Day 22 dose) after the dose. The blood samples were collected in K2-EDTA tubes and spun to plasma within one hour of collection and stored at -20°C until analysis. Palbociclib plasma concentrations were measured by a validated liquid chromatography-mass spectrometric assay method with a lower limit of quantitation of 1 ng/ml.
Non-compartmental techniques were used to analyze the concentration-time data for palbociclib. The peak plasma concentration (Cmax) and time to Cmax(tmax) were determined from the plasma concentration-time profile. The last three measurable concentration-time data points in the serial sampling window were used to define the log-linear terminal slope (β), and the terminal half-life (t1/2) was calculated as t1/2 = ln(2)/β. The area under the plasma concentration versus time curve from time zero to the last measurable sampling time point (AUC0-Tlast) was calculated using the linear-up/log-down trapezoidal rule and the area under the curve from time zero to time infinity (AUC0-∞) was calculated by extrapolating AUC0-Tlast from the last measurable time point (Clast) using β: (AUC0-Tlast + Clast / β). The BSA-normalized apparent oral clearance (CL/F) was calculated as the BSA-normalized dose divided by AUC0–∞.