The PK endpoints included the PK characteristics of each of the probe drugs administered, either as a component of the probe-drug cocktail (midazolam, S-warfarin, R-warfarin, omeprazole) or alone (digoxin), in the absence of BI 425809 in period 1 and on a background of steady-state BI 425809 in period 2. The PK characteristics of interest were area under the concentration-time curve (AUC) of the probe drug in plasma from administration (time t = 0) to the last quantifiable data point (AUC0–tz), the maximum measured concentration of the probe drug in plasma (Cmax), time from dosing to maximum measured concentration of the probe drug in plasma (tmax), and terminal half-life of the probe drug in plasma (t1/2). The attainment of BI 425809 steady state was explored by assessing trough plasma concentration immediately before the next dose (Cpre) on days 8, 9, and 10 in period 2. For BI 425809 at steady state, AUC over a uniform dosing interval (AUCτ,ss), Cmax over a uniform dosing interval (Cmax,ss), and tmax (tmax,ss) were also described. Plasma samples for probe drugs were collected on days 1 to 6 of period 1 and on days 10 to 15 of period 2. Plasma samples for BI 425809 were collected on days 1 to 4, 6, and 8 to 15 of period 2 and at the end-of-trial visit.
Plasma concentrations of BI 425809 and probe drugs were assessed using validated liquid chromatography–tandem mass spectrometry methods (details are shown in Supplementary Table S2, http://links.lww.com/JCP/A836).