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Intravenous (IV) NEPA, containing fosnetupitant, a water\u2010soluble N\u2010phosphoryloxymethyl prodrug of netupitant, has been developed. Fosnetupitant does not require excipients or solubility enhancers often used to increase IV NK<jats:sub>1<\/jats:sub>RA water solubility, preventing the occurrence of hypersensitivity and infusion\u2010site reactions associated with these products. In this phase 1 study, subjects received a 30\u2010minute placebo or fosnetupitant (17.6\u2013353\u00a0mg) infusion and an oral NEPA or placebo capsule, with 2\u2010sequence crossover treatment for fosnetupitant 118\u2010 to 353\u2010mg dose cohorts. IV fosnetupitant safety and pharmacokinetics were evaluated, and its equivalence to an oral netupitant 300\u2010mg dose was defined. Overall, 158 healthy volunteers were enrolled. All adverse events (AEs) were mild or moderate in intensity. Doppler\u2010identified infusion\u2010site asymptomatic thrombosis occurred in 5.4% (fosnetupitant) and 1.2% (oral NEPA) of subjects. The frequency or number of treatment\u2010related AEs did not increase with ascending fosnetupitant doses. The most common treatment\u2010related AEs were headache (fosnetupitant, 8.1%; oral NEPA, 12.7%) and constipation (fosnetupitant, 1.4%; oral NEPA, 7.5%). A fosnetupitant 235\u2010mg dose was equivalent, in terms of netupitant exposure, to 300\u2010mg oral netupitant. The safety profile of a single fosnetupitant 235\u2010mg infusion was similar to that of single\u2010dose oral NEPA.<\/jats:p>","DOI":"10.1002\/cpdd.1183","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T10:46:32Z","timestamp":1666262792000},"page":"1405-1418","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Challenges in the Development of Intravenous Neurokinin\u20101 Receptor Antagonists: Results of a Safety and Pharmacokinetics Dose\u2010Finding, Phase\u00a01 Study of Intravenous Fosnetupitant"],"prefix":"10.1002","volume":"11","author":[{"given":"Timothy","family":"Tyler","sequence":"first","affiliation":[{"name":"Comprehensive Cancer Center Desert Regional Medical Center  Palm Springs California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Armin","family":"Schultz","sequence":"additional","affiliation":[{"name":"CRS Clinical Research Services 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