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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Fosaprepitant is a prodrug and is rapidly metabolised to aprepitant. Aprepitant undergoes extensive hepatic metabolism, mainly via oxidation by the cytochrome P450 isoenzyme CYP3A4; the isoenzymes CYP1A2 and CYP2C19 mediate minor metabolic pathways. The resultant metabolites have weak activity and are excreted in the urine and in the faeces.
UVR-B-induced NKR-1 Expression in Ocular Tissues is blocked by Substance P Receptor Antagonist Fosaprepitant in the Exposed as well as Unexposed Partner Eye
Published in Ocular Immunology and Inflammation, 2021
Janine Gross, Alfred R. Wegener, Martin Kronschläger, Carl-Ludwig Schönfeld, Frank G. Holz, Linda M. Meyer
We previously found evidence that inflammatory processes are involved in UVR-B-induced cataract formation including an NKR-1 upregulation not only in the exposed eye but also in the unexposed partner eye in vivo.23 In order to comprehend the interrelationship between selective NKR-1 antagonists and unilateral UVR-B exposure, in the current project, we hypothesize that the treatment with NKR-1 antagonists reduces the UVR-B-induced inflammation in the exposed as well as in the contralateral partner eye leading to a decreased protein level of substance P receptor and pro-inflammatory cytokines/chemokines in both eyes. Here, we investigated Fosaprepitant/IVEMEND® and Spantide I as the NKR-1 antagonists in the established UVR-B-induced cataract mouse model. The clinical approved Fosaprepitant is the water-soluble, intravenously administered prodrug of Aprepitant24,25 rapidly converted to the active form, Aprepitant by phosphatase enzymes.26,27 Fosaprepitant is approved by the Food and Drug Administration (FDA), indicated for the prevention of nausea and vomiting after chemotherapy or post-operative surgery.28 To understand the signaling pathway of substance P and its receptor NKR-1 to the partner eye, including detailed knowledge of the non-peptide NKR-1 antagonist Fosaprepitant could offer new therapeutic treatment options and clinical preventive strategies for various eye diseases, such as UVR-B-induced cataract formation but also sympathetic ophthalmitis.
Neurokinin-1 receptor antagonists: review of their role for the prevention of chemotherapy-induced nausea and vomiting in adults
Published in Expert Review of Clinical Pharmacology, 2019
Meinolf Karthaus, Xaver Schiel, Christina H. Ruhlmann, Luigi Celio
Fosaprepitant, approved by the FDA and EMA in 2008, is rapidly converted to aprepitant, with which it shows bioequivalence and comparable activity [41,86,87]. In patients receiving high-dose cisplatin, single-dose IV fosaprepitant was as effective as the 3-day aprepitant regimen, both in combination with 5-HT3RA–dexamethasone, for preventing CINV during the overall phase [86]. Moreover, fosaprepitant–5-HT3RA–dexamethasone was significantly superior to 5-HT3RA–dexamethasone in terms of CR in the overall, acute, and delayed phases (p < 0.005) [88]. A phase 3 study in patients receiving MEC showed that a single IV dose of fosaprepitant significantly improved the CR rate in the delayed and overall periods compared with placebo-ondansetron-dexamethasone [89]. As will be discussed under safety, IV fosaprepitant formulated with polysorbate 80 has been associated with hypersensitivity reactions, including anaphylaxis, and infusion-site reactions and infusion-site AEs [90]. As a consequence, the FDA has included a warning on the label [41].
A pharmacological overview of aprepitant for the prevention of postoperative nausea and vomiting
Published in Expert Review of Clinical Pharmacology, 2023
Andrew Padilla, Ashraf S Habib
Currently, aprepitant is available orally in 40 mg, 80 mg or 125 mg formulations. The 40 mg dose is the one approved for prophylaxis of PONV, and it must be administered within 3 hours of anesthesia as it will reach maximum plasma concentration withing 3 hours [17]. Although commonly prescribed orally, two other forms of aprepitant are available. Fosaprepitant is a water-soluble phosphoryl prodrug of aprepitant that is available at 150 mg for intravenous administration. After administration, fosaprepitant is converted to aprepitant within 30 minutes [24]. Fosaprepitant is FDA-approved for the management of chemotherapy-induced nausea and vomiting (CINV), but not for PONV. Aponvie, the recently approved IV formulation of aprepitant, is prescribed at 32 mg over a 30 second injection prior to induction of anesthesia. It reaches therapeutic plasma concentrations associated with at least 97% receptor occupancy within 5 minutes of administration [18]. The approval of HTX-019 (Aponvie) was based on a randomized open-label phase 1 cross over study in 32 healthy volunteers. The study reported that the administration of a 32 mg dose as a 30 second intravenous injection had bioequivalent pharmacokinetics to those of oral aprepitant 40 mg [25]. Investigation of a nanoparticle formulation of aprepitant using in vitro dissolution studies has demonstrated improved solubility and dissolution of the drug. However, a rat single-pass intestinal perfusion model highlighted that intestinal solubility is still a barrier for the nanoparticle formulation with further investigation necessary before more robust in vivo experiments are conducted [26,27].