Physiologically Based Pharmacokinetic (PBPK) Model to Predict the Magnitude of Drug–Drug Interaction Between Fezolinetant and CYP1A2 Inhibitors

Fezolinetant is a non-hormonal, selective neurokinin 3 receptor antagonist approved in multiple countries including the United States, in Europe, and in Asia for the treatment of moderate to severe vasomotor symptoms in menopausal women. Fezolinetant is primarily metabolized by CYP1A2 and was found to be a sensitive substrate for CYP1A2 metabolism based on a clinical DDI study with strong CYP1A2 inhibitor, fluvoxamine. Therefore, coadministration with CYP1A2 inhibitors or inducers (such as smoking) could lead to changes in fezolinetant exposure. A physiological-based pharmacokinetic (PBPK) model was built for fezolinetant using the Simcyp simulator software with in vitro and in vivo data. The final verified model was used to predict fezolinetant exposure following coadministration with mexiletine (moderate CYP1A2 inhibitor), ciprofloxacin (moderate CYP1A2 inhibitor), and cimetidine (weak CYP1A2 inhibitor). Depending on the dosing regimen of the inhibitor and the meal status, coadministration with a weak CYP1A2 inhibitor, such as cimetidine, was predicted to increase fezolinetant C_max by 1.30 to 1.36 and AUC_inf by 1.61 to 2.01 fold. A moderate CYP1A2 inhibitor, such as mexiletine, was predicted to increase fezolinetant C_max by 1.36 to 1.59 fold and AUC_inf by 3.38 to 4.61 fold. Another moderate CYP1A2 inhibitor, ciprofloxacin, was predicted to increase fezolinetant C_max by 1.39 to 1.49 fold and AUC_inf by and 1.99 to 2.33 fold. The results of the PBPK analysis supported global labeling language statements for fezolinetant.