Area under the AUC from time zero extrapolated to infinity, calculated by linear up/log down trapezoidal summation. In case of anomalous predose concentration of greater than 5% of Cmax was indicated, the PK parameters for the affected analyte and given subject were excluded from the analyses. Since caffeine is contained in the plethora of foods and beverages, most subjects had predose caffeine concentrations on Day 1 and Day 22 that exceeded 5% of their Maximum plasma concentration (Cmax). Caffeine PK parameter calculations and analyses were performed using concentrations adjusted by subtracting the contribution of the predose caffeine levels at each postdose timepoint using the following equation: Concentration (adjusted) = Concentration (observed) - \[C predose \* exp(-k\*t)\], with 'k' representing the patient-specific elimination rate constant (λz) determined using observed caffeine concentration data on Day 1 and Day 22 and 't' representing the actual time postdose.

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, calculated by linear up/log down trapezoidal summation for S-warfarin (10 mg warfarin contains 5 mg S-warfarin)

Cmax for all cocktail substrates (caffeine, omeprazole, midazolam and S-warfarin), obtained directly from the observed concentration versus time data. In case of anomalous predose concentration of greater than 5% of Cmax was indicated, the PK parameters for the affected analyte and given subject were excluded from the analyses. Since caffeine is contained in the plethora of foods and beverages, most subjects had predose caffeine concentrations on Day 1 and Day 22 that exceeded 5% of their Cmax. Caffeine PK parameter calculations and analyses were performed using concentrations adjusted by subtracting the contribution of the predose caffeine levels at each postdose timepoint using the following equation: Concentration (adjusted) = Concentration (observed) - \[C predose \* exp(-k\*t)\], with 'k' representing the patient-specific elimination rate constant (λz) determined using observed caffeine concentration data on Day 1 and Day 22 and 't' representing the actual time postdose.