Drug-drug interactions of icenticaftor (QBW251) with a 5-probe cytochrome P450 cocktail and oral contraceptives.

Abstract

A drug-drug interaction (DDI) study was conducted to evaluate the effect of icenticaftor (QBW251) on the pharmacokinetics (PK) of a 5-probe cytochrome P450 (CYP) substrate cocktail, guided by invitro studies in human hepatocytes and liver microsomes. Another DDI study investigated the effect of icenticaftor on the PK and pharmacodynamics (PD) of a monophasic oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LVG) in premenopausal healthy female subjects. The static-mechanistic DDI assessment indicated that icenticaftor may moderately induce the metabolic clearance of co-medications metabolized by CYP3A4 (area under the concentration-time curve [AUC] ratio: 0.47) and potentially CYP2C; icenticaftor may also weakly inhibit the metabolic clearance of co-medications metabolized by CYP1A2 and CYP3A4 (AUC ratio: 1.35 and 1.86, respectively) and moderately inhibit CYP2B6 (AUC ratio: 2.11). In the CYP substrate cocktail DDI study, icenticaftor 300 mg twice daily (b.i.d.) moderately inhibited CYP1A2 (AUC ratio: 3.35) and CYP2C19 (AUC ratio: 2.70). As expected from the results of the invitro studies, weak induction was observed for CYP3A4 (AUC ratio: 0.51) and CYP2C8 (AUC ratio: 0.66). In the OC DDI study, co-administration of icenticaftor 450 mg b.i.d. with monophasic OC containing 30-μg EE and 150-μg LVG once daily reduced the plasma exposure of both components by approximately 50% and led to increased levels of follicle-stimulating hormone and luteinizing hormone. These results provide valuable guidance for the use of icenticaftor in patients taking concomitant medications that are substrates of CYP enzymes or patients using OCs.