PMID- 36263927
OWN - NLM
STAT- MEDLINE
DCOM- 20221208
LR  - 20230415
IS  - 2160-7648 (Electronic)
IS  - 2160-763X (Print)
IS  - 2160-763X (Linking)
VI  - 11
IP  - 12
DP  - 2022 Dec
TI  - Challenges in the Development of Intravenous Neurokinin-1 Receptor Antagonists: 
      Results of a Safety and Pharmacokinetics Dose-Finding, Phase 1 Study of 
      Intravenous Fosnetupitant.
PG  - 1405-1418
LID - 10.1002/cpdd.1183 [doi]
AB  - Oral NEPA is the fixed-combination antiemetic comprising netupitant (neurokinin-1 
      receptor antagonist [NK(1) RA]) and palonosetron (5-hydroxytryptamine-3 receptor 
      antagonist [5-HT(3) 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 NK(1) RA 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.
CI  - (c) 2022 The Authors. Clinical Pharmacology in Drug Development published by Wiley 
      Periodicals LLC on behalf of American College of Clinical Pharmacology.
FAU - Tyler, Timothy
AU  - Tyler T
AD  - Comprehensive Cancer Center, Desert Regional Medical Center, Palm Springs, 
      California, USA.
FAU - Schultz, Armin
AU  - Schultz A
AD  - CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany.
FAU - Venturini, Alessio
AU  - Venturini A
AD  - Helsinn Healthcare SA, Lugano/Pazzallo, Switzerland.
FAU - Giuliano, Claudio
AU  - Giuliano C
AD  - Helsinn Healthcare SA, Lugano/Pazzallo, Switzerland.
FAU - Bernareggi, Alberto
AU  - Bernareggi A
AD  - Helsinn Healthcare SA, Lugano/Pazzallo, Switzerland.
FAU - Spezia, Riccardo
AU  - Spezia R
AD  - Helsinn Healthcare SA, Lugano/Pazzallo, Switzerland.
FAU - Voisin, Daniel
AU  - Voisin D
AD  - Helsinn Healthcare SA, Lugano/Pazzallo, Switzerland.
FAU - Stella, Valentino
AU  - Stella V
AD  - Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20221020
PL  - United States
TA  - Clin Pharmacol Drug Dev
JT  - Clinical pharmacology in drug development
JID - 101572899
RN  - 7732P08TIR (netupitant)
RN  - 0 (Neurokinin-1 Receptor Antagonists)
RN  - 059QF0KO0R (Water)
SB  - IM
MH  - Humans
MH  - *Nausea/chemically induced
MH  - *Neurokinin-1 Receptor Antagonists/adverse effects
MH  - Vomiting/chemically induced
MH  - Water
PMC - PMC10092591
OTO - NOTNLM
OT  - 5-hydroxytryptamine-3 receptor antagonists
OT  - chemotherapy-induced nausea and vomiting
OT  - fosnetupitant
OT  - injection site reactions
OT  - intravenous formulation
OT  - netupitant
OT  - neurokinin-1 receptor antagonists
OT  - palonosetron
OT  - prodrug
COIS- Timothy Tyler: speaker for MorphoSys/Incyte, G1 Therapeutics, Alexion, Sanofi 
      Genzyme, Pfizer Biosimilars, Genentech, Amgen/Onyx, and BMS; consultant for 
      TerSera, Sandoz, and Secura Bio; advisory board member for Corvida Medical, C.S. 
      Lewis Foundation. Armin Schultz: CRS Mannheim GmbH employee. Alessio Venturini: 
      Former Helsinn employee. Claudio Giuliano: Helsinn employee. Alberto Bernareggi: 
      Helsinn employee. Riccardo Spezia: Helsinn employee at the time of study conduct 
      and current freelance consultant for Helsinn. Daniel Voisin: Helsinn employee. 
      Valentino Stella: consultant for Helsinn. Helsinn Healthcare SA participated in 
      the design of the study; collection, analysis, and interpretation of data; 
      approval of the manuscript; and the decision to submit the article for 
      publication
EDAT- 2022/10/21 06:00
MHDA- 2022/12/03 06:00
PMCR- 2023/04/12
CRDT- 2022/10/20 06:52
PHST- 2022/03/24 00:00 [received]
PHST- 2022/09/18 00:00 [accepted]
PHST- 2022/10/21 06:00 [pubmed]
PHST- 2022/12/03 06:00 [medline]
PHST- 2022/10/20 06:52 [entrez]
PHST- 2023/04/12 00:00 [pmc-release]
AID - CPDD1183 [pii]
AID - 10.1002/cpdd.1183 [doi]
PST - ppublish
SO  - Clin Pharmacol Drug Dev. 2022 Dec;11(12):1405-1418. doi: 10.1002/cpdd.1183. Epub 
      2022 Oct 20.