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

• Published in: British journal of clinical pharmacology Vol. 90; no. 8; pp. 2004 - 2018
• Main Authors: Friedrich, Christian, Singh, Dave, Francke, Klaus, Klein, Stefan, Hetzel, Terence, Zolk, Oliver, Gashaw, Isabella, Scheerans, Christian, Morice, Alyn
• Format: Journal Article
• Language: English
• Published: England 01.08.2024
• Subjects: Adolescent; Adult; assessment of taste function; Cough - chemically induced; cough‐reflex sensitivity; Cytochrome P-450 CYP3A - metabolism; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Healthy Volunteers; Humans; Male; Midazolam - administration & dosage; Midazolam - adverse effects; Midazolam - pharmacokinetics; Middle Aged; Purinergic P2X Receptor Antagonists - administration & dosage; Purinergic P2X Receptor Antagonists - adverse effects; Purinergic P2X Receptor Antagonists - pharmacokinetics; Purinergic P2X Receptor Antagonists - pharmacology; purinergic receptors; receptor pharmacology; Receptors, Purinergic P2X3 - drug effects; Receptors, Purinergic P2X3 - metabolism; refractory chronic cough; Taste - drug effects; taste disturbances; taste strips; Young Adult; cough‐reflex sensitivity; purinergic receptors; receptor pharmacology; assessment of taste function; refractory chronic cough; taste disturbances; taste strips
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.16091

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.