Investigating Sulfotransferase Mediated Drug Interactions of Ethinylestradiol using a Physiologically Based...

Ethinylestradiol (EE) is a common estrogen used in combined oral contraceptives. CYP3A4 and SULT1E1 are the major enzymes that metabolize EE, while CYP2C9 and UGT1A1 have minor contributions. Drug-drug interactions (DDIs) mediated by inhibition or induction of metabolism can adversely impact the safety and efficacy of EE. A physiologically-based pharmacokinetic (PBPK) model was previously developed and extensively verified to predict CYP3A4-mediated DDIs of EE. Recent clinical evidence showed increased EE exposure following coadministration with the SULT1E1 inhibitors etoricoxib and ziritaxestat, highlighting the need to expand the PBPK model to allow for predictions of SULT1E1-mediated DDIs. A PBPK model including SULT metabolism of EE was constructed and the interactions with PBPK models developed for etoricoxib and ziritaxestat were simulated. The observed EE concentrations were within the simulated 95% percentiles for the control and the DDI scenario. The predicted ratios for peak concentration (C_max) and area under concentration-time curve (AUCt) were within 1.5-fold of the observed data. The simulations demonstrated that clinically relevant DDIs may not be expected when EE is co-administered with 120 mg etoricoxib QD but may be expected with 600 mg QD ziritaxestat QD. A simulated dose reduction from 35 µg to 20 µg, when co-administered with ziritaxestat, was predicted to produce EE exposures in a similar range to when 35 µg is administered alone. The developed PBPK models for etoricoxib and ziritaxestat can be used in future applications as probe SULT1E1 precipitants. Incorporation of SULT metabolism into the EE PBPK model may support a more comprehensive assessment of the DDI liability of investigational drugs that affect multiple EE metabolic pathways.