Challenges in the Development of Intravenous Neurokinin‐1 Receptor Antagonists: Results of a Safety and Pharmacokinetics Dose‐Finding, Phase 1 Study of Intravenous Fosnetupitant

• Published in: Clinical pharmacology in drug development Vol. 11; no. 12; pp. 1405 - 1418
• Main Authors: Tyler, Timothy, Schultz, Armin, Venturini, Alessio, Giuliano, Claudio, Bernareggi, Alberto, Spezia, Riccardo, Voisin, Daniel, Stella, Valentino
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.12.2022; John Wiley and Sons Inc
• Subjects: 5‐hydroxytryptamine‐3 receptor antagonists; chemotherapy‐induced nausea and vomiting; fosnetupitant; Humans; injection site reactions; intravenous formulation; Nausea - chemically induced; netupitant; Neurokinin-1 Receptor Antagonists - adverse effects; neurokinin‐1 receptor antagonists; Original; palonosetron; Pharmacokinetics; prodrug; Vomiting - chemically induced; Water; prodrug; 5-hydroxytryptamine-3 receptor antagonists; neurokinin-1 receptor antagonists; intravenous formulation; netupitant; fosnetupitant; palonosetron; chemotherapy-induced nausea and vomiting; injection site reactions
• ISSN: 2160-763X; 2160-7648; 2160-7648
• DOI: 10.1002/cpdd.1183

Oral NEPA is the fixed‐combination antiemetic comprising netupitant (neurokinin‐1 receptor antagonist [NK1RA]) and palonosetron (5‐hydroxytryptamine‐3 receptor antagonist [5‐HT3 RA]). Intravenous (IV) NEPA, containing fosnetupitant, a water‐soluble N‐phosphoryloxymethyl prodrug of netupitant, has been developed. Fosnetupitant does not require excipients or solubility enhancers often used to increase IV NK1RA water solubility, preventing the occurrence of hypersensitivity and infusion‐site reactions associated with these products. In this phase 1 study, subjects received a 30‐minute placebo or fosnetupitant (17.6–353 mg) infusion and an oral NEPA or placebo capsule, with 2‐sequence crossover treatment for fosnetupitant 118‐ to 353‐mg dose cohorts. IV fosnetupitant safety and pharmacokinetics were evaluated, and its equivalence to an oral netupitant 300‐mg dose was defined. Overall, 158 healthy volunteers were enrolled. All adverse events (AEs) were mild or moderate in intensity. Doppler‐identified infusion‐site asymptomatic thrombosis occurred in 5.4% (fosnetupitant) and 1.2% (oral NEPA) of subjects. The frequency or number of treatment‐related AEs did not increase with ascending fosnetupitant doses. The most common treatment‐related AEs were headache (fosnetupitant, 8.1%; oral NEPA, 12.7%) and constipation (fosnetupitant, 1.4%; oral NEPA, 7.5%). A fosnetupitant 235‐mg dose was equivalent, in terms of netupitant exposure, to 300‐mg oral netupitant. The safety profile of a single fosnetupitant 235‐mg infusion was similar to that of single‐dose oral NEPA.