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–∞.