Safety, Tolerability, and Pharmacokinetics of Filapixant, a Highly Selective P2X3 Receptor Antagonist, in an Ascending-Single-Dose First-in-Human Study
<b>Background/Objectives:</b> P2X3 receptor antagonists have been suggested as a potential treatment for urogenital, respiratory and pain conditions. This first-in-human (FiH) study evaluated filapixant, a new P2X3 receptor antagonist with high receptor selectivity. It was anticipated th...
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MDPI AG
2025-05-01
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| Online Access: | https://www.mdpi.com/1424-8247/18/5/758 |
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| author | Klaus Francke Sybille Baumann Isabella Gashaw Stefan Klein Beate Rohde Oliver Zolk Oliver M. Fischer Christian Friedrich |
| author_facet | Klaus Francke Sybille Baumann Isabella Gashaw Stefan Klein Beate Rohde Oliver Zolk Oliver M. Fischer Christian Friedrich |
| author_sort | Klaus Francke |
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| description | <b>Background/Objectives:</b> P2X3 receptor antagonists have been suggested as a potential treatment for urogenital, respiratory and pain conditions. This first-in-human (FiH) study evaluated filapixant, a new P2X3 receptor antagonist with high receptor selectivity. It was anticipated that filapixant would cause fewer taste-related side effects compared to the unselective P2X3/P2X2/3 antagonist gefapixant and the less selective P2X3 antagonist eliapixant. This study assessed the tolerability, safety and PK of filapixant, the effect of food on PK and relative BA of a tablet vs. solution. <b>Methods</b>: This study (NCT03212586) followed a randomized, double-blind single-ascending-dose design. A total of 72 healthy male subjects received a solution (6–60 mg) or immediate-release tablets (120–1250 mg) of filapixant or corresponding placebo in fasted state. The subjects at 60 mg were re-dosed with 60 mg tablets in both fasted and fed states. The endpoints included PK parameters, dose proportionality, adverse events, and taste assessments (taste strips; dysgeusia questionnaire). <b>Results</b>: Filapixant showed dose-proportional PK with a half-life (about 10–15 h), supporting once-daily dosing. Food minimally affected PK and BA was comparable between tablet and solution. Filapixant was well tolerated; however, the number of taste side effects was unexpectedly high. Comparing the results observed across clinical filapixant studies, the threshold for such side effects seems to be well below the in vitro IC<sub>50</sub> for P2X2/3. <b>Conclusions</b>: Treatment with filapixant was safe and well tolerated. Filapixant showed dose-proportional PK, bioavailability similar to that of a solution and a tablet, and a minor effect of food on PK. The number of taste side effects was unexpectedly high considering the high in vitro P2X3 receptor selectivity. Factors other than selectivity are needed to explain taste profile differences between P2X3 antagonists. |
| format | Article |
| id | doaj-art-fb4f1d4dcd024a6793aad16eb3dfba42 |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-fb4f1d4dcd024a6793aad16eb3dfba422025-08-20T03:47:58ZengMDPI AGPharmaceuticals1424-82472025-05-0118575810.3390/ph18050758Safety, Tolerability, and Pharmacokinetics of Filapixant, a Highly Selective P2X3 Receptor Antagonist, in an Ascending-Single-Dose First-in-Human StudyKlaus Francke0Sybille Baumann1Isabella Gashaw2Stefan Klein3Beate Rohde4Oliver Zolk5Oliver M. Fischer6Christian Friedrich7Bayer AG, 13353 Berlin, GermanyCRS Clinical Research Services Berlin GmbH, 13627 Berlin, GermanyBayer AG, 13353 Berlin, GermanyBayer AG, 13353 Berlin, GermanyBayer AG, 13353 Berlin, GermanyInstitute of Clinical Pharmacology, Brandenburg Medical School, Immanuel Klinik Rüdersdorf, Seebad 82/83, Rüdersdorf bei Berlin, 15562 Rüdersdorf, GermanyBayer AG, 13353 Berlin, GermanyBayer AG, 13353 Berlin, Germany<b>Background/Objectives:</b> P2X3 receptor antagonists have been suggested as a potential treatment for urogenital, respiratory and pain conditions. This first-in-human (FiH) study evaluated filapixant, a new P2X3 receptor antagonist with high receptor selectivity. It was anticipated that filapixant would cause fewer taste-related side effects compared to the unselective P2X3/P2X2/3 antagonist gefapixant and the less selective P2X3 antagonist eliapixant. This study assessed the tolerability, safety and PK of filapixant, the effect of food on PK and relative BA of a tablet vs. solution. <b>Methods</b>: This study (NCT03212586) followed a randomized, double-blind single-ascending-dose design. A total of 72 healthy male subjects received a solution (6–60 mg) or immediate-release tablets (120–1250 mg) of filapixant or corresponding placebo in fasted state. The subjects at 60 mg were re-dosed with 60 mg tablets in both fasted and fed states. The endpoints included PK parameters, dose proportionality, adverse events, and taste assessments (taste strips; dysgeusia questionnaire). <b>Results</b>: Filapixant showed dose-proportional PK with a half-life (about 10–15 h), supporting once-daily dosing. Food minimally affected PK and BA was comparable between tablet and solution. Filapixant was well tolerated; however, the number of taste side effects was unexpectedly high. Comparing the results observed across clinical filapixant studies, the threshold for such side effects seems to be well below the in vitro IC<sub>50</sub> for P2X2/3. <b>Conclusions</b>: Treatment with filapixant was safe and well tolerated. Filapixant showed dose-proportional PK, bioavailability similar to that of a solution and a tablet, and a minor effect of food on PK. The number of taste side effects was unexpectedly high considering the high in vitro P2X3 receptor selectivity. Factors other than selectivity are needed to explain taste profile differences between P2X3 antagonists.https://www.mdpi.com/1424-8247/18/5/758dysgeusiaP2X3 receptor antagonistspharmacokineticstaste perceptionfirst in human |
| spellingShingle | Klaus Francke Sybille Baumann Isabella Gashaw Stefan Klein Beate Rohde Oliver Zolk Oliver M. Fischer Christian Friedrich Safety, Tolerability, and Pharmacokinetics of Filapixant, a Highly Selective P2X3 Receptor Antagonist, in an Ascending-Single-Dose First-in-Human Study Pharmaceuticals dysgeusia P2X3 receptor antagonists pharmacokinetics taste perception first in human |
| title | Safety, Tolerability, and Pharmacokinetics of Filapixant, a Highly Selective P2X3 Receptor Antagonist, in an Ascending-Single-Dose First-in-Human Study |
| title_full | Safety, Tolerability, and Pharmacokinetics of Filapixant, a Highly Selective P2X3 Receptor Antagonist, in an Ascending-Single-Dose First-in-Human Study |
| title_fullStr | Safety, Tolerability, and Pharmacokinetics of Filapixant, a Highly Selective P2X3 Receptor Antagonist, in an Ascending-Single-Dose First-in-Human Study |
| title_full_unstemmed | Safety, Tolerability, and Pharmacokinetics of Filapixant, a Highly Selective P2X3 Receptor Antagonist, in an Ascending-Single-Dose First-in-Human Study |
| title_short | Safety, Tolerability, and Pharmacokinetics of Filapixant, a Highly Selective P2X3 Receptor Antagonist, in an Ascending-Single-Dose First-in-Human Study |
| title_sort | safety tolerability and pharmacokinetics of filapixant a highly selective p2x3 receptor antagonist in an ascending single dose first in human study |
| topic | dysgeusia P2X3 receptor antagonists pharmacokinetics taste perception first in human |
| url | https://www.mdpi.com/1424-8247/18/5/758 |
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