A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug-Drug Interaction Perpetrators

The antifungal ketoconazole, which is mainly used for dermal infections and treatment of Cushing's syndrome, is prone to drug-food interactions (DFIs) and is well known for its strong drug-drug interaction (DDI) potential. Some of ketoconazole's potent inhibitory activity can be attributed to its metabolites that predominantly accumulate in the liver. This work aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model of ketoconazole and its metabolites for fasted and fed states and to investigate the impact of ketoconazole's metabolites on its DDI potential. The parent-metabolites model was developed with PK-Sim((R)) and MoBi (R) using 53 plasma concentration-time profiles. With 7 out of 7 (7/7) DFI AUC(last) and DFI C-max ratios within two-fold of observed ratios, the developed model demonstrated good predictive performance under fasted and fed conditions. DDI scenarios that included either the parent alone or with its metabolites were simulated and evaluated for the victim drugs alfentanil, alprazolam, midazolam, triazolam, and digoxin. DDI scenarios that included all metabolites as reversible inhibitors of CYP3A4 and P-gp performed best: 26/27 of DDI AUC(last) and 21/21 DDI C-max ratios were within two-fold of observed ratios, while DDI models that simulated only ketoconazole as the perpetrator underperformed: 12/27 DDI AUC(last) and 18/21 DDI C-max ratios were within the success limits.