{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T18:55:57Z","timestamp":1787684157004,"version":"build-2784847793"},"reference-count":13,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hypersensitized P2X3 receptor signaling has been described to play a role in several disorders, including chronic cough. The goal of our in vitro and in vivo studies was to investigate the biotransformation and the influence of CYP3A4 inhibition on the pharmacokinetics of the selective P2X3 antagonist filapixant. Metabolic turnover of filapixant in human liver microsomes and hepatocytes was moderate to high, indicating a complex metabolic pattern with mainly oxidative biotransformation. In recombinant CYP enzymes, depletion of filapixant was observed mainly with CYP3A4 and, to a significantly lesser extent, with CYP1A1, 2D6, 2J2, and 3A5. Drug depletion of [3H]filapixant and metabolite formation in human liver microsomes was significantly inhibited in the presence of strong CYP3A4 inhibitors, whereas other CYP isoform\u2013selective inhibitors showed no or very minor effects. Co-administration of multiple daily doses of 200 mg itraconazole with 80 mg filapixant in humans increased the AUC and Cmax of filapixant to 4.01 and 1.89-fold, respectively, indicating that filapixant is a moderately sensitive CYP3A4 substrate. Co-administration of itraconazole also prolonged the half-life of filapixant from 12.1 h to 22.8 h. Overall, changes in AUC, Cmax, and half-life indicate that both the bioavailability and elimination of filapixant were affected. Filapixant was well tolerated alone and in combination with itraconazole.<\/jats:p>","DOI":"10.3390\/ijms262010177","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T09:23:34Z","timestamp":1760952214000},"page":"10177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Investigation of the Relevance of CYP3A4 Inhibition on the Pharmacokinetics of the Novel P2X3 Antagonist Filapixant: Results of In Vitro Explorations and a Fixed-Sequence Clinical Trial with Itraconazole in Healthy Volunteers"],"prefix":"10.3390","volume":"26","author":[{"given":"Klaus","family":"Francke","sequence":"first","affiliation":[{"name":"Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Rottmann","sequence":"additional","affiliation":[{"name":"Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Klein","sequence":"additional","affiliation":[{"name":"Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8030-0051","authenticated-orcid":false,"given":"Joachim","family":"H\u00f6chel","sequence":"additional","affiliation":[{"name":"Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8955-4808","authenticated-orcid":false,"given":"Christian","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany"},{"name":"MHB-Medizinische Hochschule Brandenburg, 14770 Brandenburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2004240","DOI":"10.1183\/13993003.04240-2020","article-title":"Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: A randomised, placebo-controlled, crossover phase 2a study","volume":"58","author":"Morice","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s12931-023-02384-8","article-title":"The P2X3 Receptor Antagonist Filapixant in Patients with Refractory Chronic Cough: A Randomized Controlled Trial","volume":"24","author":"Friedrich","year":"2023","journal-title":"Respir. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1111\/bcp.16091","article-title":"Pharmacodynamics, Pharmacokinetics and CYP3A4 Interaction Potential of the Selective P2X3 Receptor Antagonist Filapixant: A Randomized Multiple Ascending-dose Study in Healthy Young Men","volume":"90","author":"Friedrich","year":"2024","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_4","unstructured":"European Medicines Agency (2025, June 01). Guideline on the Investigation of Drug Interactions. Available online: www.ema.europa.eu\/contact."},{"key":"ref_5","unstructured":"Food and Drug Administration (2025, June 01). Clinical Drug Interaction Studies-Cytochrome P450 Enzyme-and Transporter-Mediated Drug Interactions Guidance for Industry, Available online: https:\/\/www.fda.gov\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/default.htm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1128\/AAC.32.9.1310","article-title":"Pharmacokinetics of Itraconazole Following Oral Administration to Normal Volunteers","volume":"32","author":"Hardin","year":"1988","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4552","DOI":"10.1111\/bcp.15358","article-title":"First-in-human Study of Eliapixant (BAY 1817080), a Highly Selective P2X3 Receptor Antagonist: Tolerability, Safety and Pharmacokinetics","volume":"88","author":"Klein","year":"2022","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1007\/s40262-022-01126-1","article-title":"Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study","volume":"61","author":"Friedrich","year":"2022","journal-title":"Clin. Pharmacokinet."},{"key":"ref_9","unstructured":"(Harmonised Tripartite Guideline, Guideline for Good Clinical Practice E6 (R2), 2016). The International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Harmonised Tripartite Guideline, Guideline for Good Clinical Practice E6 (R2)."},{"key":"ref_10","unstructured":"Principles on Good Laboratory Practice, OECD (ENV\/MC\/CHEM(98)17)."},{"key":"ref_11","unstructured":"G.I.W.G. European Medicines Agency (Reflection Paper for Laboratories that Perform the Analysis or Evaluation of Clinical Trial Samples, 2012). 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Guideline on Bioanalytical Method Validation."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/10177\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T09:24:09Z","timestamp":1760952249000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/10177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,20]]},"references-count":13,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms262010177"],"URL":"https:\/\/doi.org\/10.3390\/ijms262010177","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,20]]}}}