Huth, Felix, Glaenzel, Ulrike, Drollmann, Anton Franz, Weis, Wendy, Zack, Julia and Bebrevska, Lidiya (2024) Pharmacokinetics of the interaction of icenticaftor (QBW251) with multiple substrates. Clinical and translational science. ISSN 1752-8062

Abstract

Icenticaftor (QBW251) is an orally administered potentiator of the cystic fibrosis transmembrane conductance regulator that is being developed as add-on therapy for the treatment of patients with chronic obstructive pulmonary disease and chronic bronchitis. A drug-drug interaction (DDI) study was conducted to evaluate the effect of icenticaftor on the pharmacokinetics (PK) of a 5 probe cytochrome P450 (CYP) substrate cocktail; this was guided by in vitro studies in human hepatocytes and liver microsomes. A second 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 induce the metabolic clearance of co-medications metabolized by CYP3A4 and potentially CYP2C; icenticaftor may also inhibit the metabolic clearance of co-medications metabolized by CYP1A2, CYP2B6, and CYP3A4/5. In the CYP substrate cocktail DDI study, icenticaftor 300 mg twice daily (b.i.d.) moderately inhibited CYP1A2 and CYP2C19. As expected from the results of the in vitro studies, weak induction was observed for CYP3A4 and CYP2C8. 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 those using OCs.

Item Type:	Article
Date Deposited:	11 Mar 2025 00:45
Last Modified:	11 Mar 2025 00:45
URI:	https://oak.novartis.com/id/eprint/53857