Assessing Drug-Drug Interaction and Food Effect for BCS Class 2 Compound BI 730357 (Retinoic Acid-Related Orphan...

Background: The drug candidate BI 730357 is a Biopharmaceutics Classification System (BCS) Class II compound showing atypical absorption after oral administration in fasted and fed healthy individuals, for which conventional traditional deconvolution methods could not explain formulation dependencies. Methods: A physiologically based pharmacokinetic (PBPK) model of BI 730357 was developed using the Open Systems Pharmacology (OSP) PBPK software tool PK-Sim^®, which could describe the pharmacokinetics in fasted and fed subjects after single and multiple doses. A Weibull function was used to describe the in vivo formulation kinetics, whereas colonic absorption was adopted as the main driver to describe the late phases of observed pharmacokinetics after oral administration. The food effect was applied using the implemented feature PK-Sim^®. Results: The model accurately predicted an observed itraconazole drug-drug interaction (DDI) in fasted subjects and was used to explore the effects of the strong CYP3A4 inducer rifampicin on the pharmacokinetics of BI 730357 after administration in fed subjects. Conclusions: The combined results suggest that the BI 730357 PBPK model with semi-mechanistic absorption can prospectively explore the effects of CYP3A4 inhibitors and inducers on the pharmacokinetics after administration in fed or fasted subjects within the given dose range.