Discussion
In this study, adavosertib exposure, when given alone or co-administered with the cocktail drugs, was similar to that observed in previous studies when given alone [A physiologically based PK (PBPK) model (based on in vitro studies of absorption, distribution, metabolism, and excretion, clinical adavosertib PK data for doses of 175–300 mg once daily [qd] or bid, and multiple dosing schedules [3 days on/4 days off and 5 days on/9 days off]) to assess multifaceted CYP modulation predicted that adavosertib is mainly metabolized by CYP3A with an FMO3 and/or FMO5 component and is a time-dependent (irreversible) inhibitor of CYP3A and a weak reversible (direct) inhibitor of CYP2C8, CYP2C9, and CYP2C19 [The observed safety profile of adavosertib in this study was concordant with that found in previous clinical studies [Although the study was terminated early because of the difficulty in enrolling patients (i.e. screening/rescreening failures) and evaluable data not being available for all enrolled patients (as a result of protocol deviations/events), this had minimal impact on the interpretation of the PK results. Overall, the data from evaluable patients were adequate and representative of the primary objective of assessing the DDI potential of adavosertib. Instances of pre-dose concentrations > 5% of COverall, the results from this study suggest that adavosertib is a weak inhibitor of CYP1A2, CYP2C19, and CYP3A according to the US FDA guidance for definition of a weak inhibitor [