Pharmacodynamics, pharmacokinetics and CYP3A4 interaction potential of the selective P2X3 receptor antagonist filapixant: A randomized multiple ascending-dose study in healthy young men

Friedrich, Christian; Singh, Dave; Francke, Klaus; Klein, Stefan; Hetzel, Terence; Zolk, Oliver; Gashaw, Isabella; Scheerans, Christian; Morice, Alyn

Abstract

Aims: We report on investigations exploring the P2X3-receptor antagonist filapixant's effect on taste perception and cough-reflex sensitivity and describe its pharmacokinetics, including its CYP3A4-interaction potential. Methods: In a randomized, placebo-controlled, double-blind study, 3 × 12 healthy men (18-45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2 weeks. A single dose of midazolam (1 mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste-strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments. Results: Taste disturbances were observed mainly in the 250-mg group: six of nine participants (67%) in this group reported hypo- or dysgeusia in the questionnaire; eight participants (89%) reported taste-related adverse events. Five participants (56%) had a decrease in overall taste-strips-test scores ≥2 points (point estimate −1.1 points, 90% confidence interval [−3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co-administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration-time curve ratios and 90% confidence intervals were within 80-125%. No serious or severe adverse events were reported. Conclusions: Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor-selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough-challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential.

Citation

Friedrich, C., Singh, D., Francke, K., Klein, S., Hetzel, T., Zolk, O., Gashaw, I., Scheerans, C., & Morice, A. (2024). Pharmacodynamics, pharmacokinetics and CYP3A4 interaction potential of the selective P2X3 receptor antagonist filapixant: A randomized multiple ascending-dose study in healthy young men. British Journal of Clinical Pharmacology, https://doi.org/10.1111/bcp.16091

• Journal Article Type: Article
• Acceptance Date: May 22, 2024
• Publication Date: Jan 1, 2024
• Deposit Date: Sep 17, 2024
• Publicly Available Date: Sep 23, 2024
• Journal: British Journal of Clinical Pharmacology
• Print ISSN: 0306-5251
• Electronic ISSN: 1365-2125
• Publisher: British Pharmacological Society
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1111/bcp.16091
• Public URL: https://hull-repository.worktribe.com/output/4700783