Mass Balance and Metabolic Pathways of Eliapixant, a P2X3 Receptor Antagonist, in Healthy Male Volunteers

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 49; no. 1; pp. 71 - 85
• Main Authors: Reif, Stefanie, Schultze-Mosgau, Marcus-Hillert, Engelen, Anna, Piel, Isabel, Denner, Karsten, Roffel, Ad, Tiessen, Renger, Klein, Stefan, Francke, Klaus, Rottmann, Antje
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 2024
• Subjects: Administration, Oral; Biomedical and Life Sciences; Biomedicine; Chromatography, High Pressure Liquid - methods; Feces - chemistry; Healthy Volunteers; Human Physiology; Humans; Male; Mass Spectrometry; Medical Biochemistry; Metabolic Networks and Pathways; NCT; NCT02817100; NCT03310645; NCT04487431; Original Research Article; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Purinergic P2X Receptor Antagonists; Volunteers
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/s13318-023-00866-0

Background Overactive adenosine triphosphate signaling via P2X3 homotrimeric receptors is implicated in multiple conditions. To fully understand the metabolism and elimination pathways of eliapixant, a study was conducted to assess the pharmacokinetics, mass balance, and routes of excretion of a single oral dose of the selective P2X3 receptor antagonist eliapixant, in addition to an in vitro characterization. Methods In this single-center open-label non-randomized non-placebo-controlled phase I study, healthy male subjects ( n  = 6) received a single dose of 50 mg eliapixant blended with 3.7 MBq [ 14 C]eliapixant as a PEG 400-based oral solution. Total radioactivity and metabolites excreted in urine and feces, and pharmacokinetics of total radioactivity, eliapixant, and metabolites in plasma were assessed via liquid scintillation counting and high-performance liquid chromatography-based methods coupled to radiometric and mass spectrometric detection. Metabolite profiles of eliapixant in human in vitro systems and metabolizing enzymes were also investigated. Results After administration as an oral solution, eliapixant was rapidly absorbed, reaching maximum plasma concentrations within 2 h. Eliapixant was eliminated from plasma with a mean terminal half-life of 48.3 h. Unchanged eliapixant was the predominant component in plasma (72.6% of total radioactivity area under the curve). The remaining percentage of drug-related components in plasma probably represented the sum of many metabolites, detected in trace amounts. Mean recovery of total radioactivity was 97.9% of the administered dose (94.3–99.4%) within 14 days, with 86.3% (84.8–88.1%) excreted via feces and 11.6% (9.5–13.1%) via urine. Excretion of parent drug was minimal in feces (0.7% of dose) and urine (≈ 0.5%). In feces, metabolites formed by oxidation represented > 90% of excreted total radioactivity. The metabolites detected in the in vitro experiments were similar to those identified in vivo. Conclusion Complete recovery of administered eliapixant-related radioactivity was observed in healthy male subjects with predominant excretion via feces. Eliapixant was almost exclusively cleared by oxidative biotransformation (> 90% of dose), with major involvement of cytochrome P450 3A4. Excretion of parent drug was of minor importance (~ 1% of dose). Clinical trial registration ClinicalTrials.gov: NCT04487431 (registered 27 July 2020)/EudraCT number: 2020-000519-54 (registered 3 February 2020), NCT02817100 (registered 26 June 2016), NCT03310645 (registered 16 October 2017). Plain Language Summary Eliapixant is a drug that acts on structures in the body called P2X3 receptors that are involved in several conditions, including chronic cough, overactive bladder, and endometriosis-related pain. When evaluating a new drug, it is important to know how it is being removed from the body by natural mechanisms. We performed a study in which six healthy male volunteers took a single dose of eliapixant, and we investigated what happened to the drug after it was taken. We measured the amount of eliapixant in the volunteers’ blood, urine, and feces, and also measured the compounds formed when eliapixant was broken down naturally by the body (“metabolites”). We also used human cells in the laboratory to investigate how the different metabolites of eliapixant are formed. Almost three-quarters of eliapixant in the blood had not been broken down at all, while the remaining one-quarter had been converted into many different metabolites. A total of 2 weeks after taking eliapixant, almost all of it had been converted to metabolites and eliminated from the body (mostly in feces, but also a small amount in urine). The most important organ for breaking down eliapixant is the liver. The information from this study will help doctors determine whether eliapixant is likely to interfere with other drugs taken simultaneously, and whether patients with liver or kidney problems might take longer than healthy people to remove it from their bodies.