Serial whole blood samples for pharmacokinetic analysis of ribociclib were collected in two 2 mL EDTA tubes during the first cycle of treatment, 30 minutes before and 0.5, 1, 2, 4, 6, and 8 hours after administration of ribociclib on day 8 and day 14 of the first cycle of treatment. Plasma was isolated by centrifugation at 1,500 × g for 10 minutes within 30 minutes following blood collection and aliquots (2 ml each) were placed in ice immediately and then stored frozen at −70°C or below until analyzed. The plasma concentration of ribociclib was determined using a liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay. Quality assurance was maintained by injecting quality control samples each time patient samples were assayed.
Plasma concentration-time data were analyzed by standard non-compartmental methods using the program WinNonlin (Pharsight, Mountain View, CA). The areas under the plasma concentration time curve (AUC) on day 8 and day 14 were calculated by trapezoidal approximation. The accumulation ratio (R) was calculated as the ratio of day 14 AUC0–8h versus the day 8 AUC0–8h. The apparent elimination half-life (t1/2) was calculated as −(0.693*τ)/ln((R−1)/R) where R is accumulation ratio and τ is the dosing interval (24 hours). Since a 24-hour blood sample was not drawn on day 14, the 24-hour plasma concentration after ribociclib administration was estimated to be equivalent to the pre-dose concentration based on the assumption that steady-state was reached on day 14, and the AUC over the 24-hour dosing interval on day 14 (AUCt) was calculated by trapezoidal approximation. Oral steady-state clearance (CLSS/F) was calculated using the equation, CLSS/F = Dose/AUCt, where dose is the administered dose of ribociclib. Standard descriptive statistics were used to summarize plasma ribociclib PK parameters.
Plasma concentration-time data were analyzed by standard non-compartmental methods using the program WinNonlin (Pharsight, Mountain View, CA). The areas under the plasma concentration time curve (AUC) on day 8 and day 14 were calculated by trapezoidal approximation. The accumulation ratio (R) was calculated as the ratio of day 14 AUC0–8h versus the day 8 AUC0–8h. The apparent elimination half-life (t1/2) was calculated as −(0.693*τ)/ln((R−1)/R) where R is accumulation ratio and τ is the dosing interval (24 hours). Since a 24-hour blood sample was not drawn on day 14, the 24-hour plasma concentration after ribociclib administration was estimated to be equivalent to the pre-dose concentration based on the assumption that steady-state was reached on day 14, and the AUC over the 24-hour dosing interval on day 14 (AUCt) was calculated by trapezoidal approximation. Oral steady-state clearance (CLSS/F) was calculated using the equation, CLSS/F = Dose/AUCt, where dose is the administered dose of ribociclib. Standard descriptive statistics were used to summarize plasma ribociclib PK parameters.
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