MedKoo product information:

Fosaprepitant  

Description of Fosaprepitant: Fosaprepitant (Emend for Injection (US), Ivemend (EU)) is an antiemetic drug, administered intravenously. It is a prodrug of aprepitant. Fosaprepitant was developed by Merck & Co. and was approved by the United States Food and Drug Administration (FDA) on January 25, 2008,  and by the European Medicines Agency (EMA) on January 11 of the same year. Merck is developing this drug for chemotherapy-induced nausea and vomiting (CINV) in adolescents, children and infants. (Phase 1 as of 2011).

Drug desciption:

EMEND (fosaprepitant dimeglumine) for Injection is a sterile, lyophilized prodrug of aprepitant, a substance P/neurokinin-1 (NK1) receptor antagonist, and is chemically described as 1-Deoxy-1(methylamino)-D-glucitol[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate (2:1) (salt).  Its empirical formula is C23H22F7N4O6P • 2(C7H17NO5).

Fosaprepitant dimeglumine is a white to off-white amorphous powder with a molecular weight of 1004.83. It is freely soluble in water. EMEND (fosaprepitant dimeglumine injection) for Injection is a lyophilized prodrug of aprepitant containing polysorbate 80 (PS80), to be administered intravenously as an infusion.  Each vial of EMEND (fosaprepitant dimeglumine injection) for Injection 115 mg for intravenous administration contains 188 mg of fosaprepitant dimeglumine equivalent to 115 mg of fosaprepitant free acid and the following inactive ingredients: edetate disodium (14.4 mg), polysorbate 80 (57.5 mg), lactose anhydrous (287.5 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment). Each vial of EMEND (fosaprepitant dimeglumine injection) for Injection 150 mg for intravenous administration contains 245.3 mg of fosaprepitant dimeglumine equivalent to 150 mg of fosaprepitant free acid and the following inactive ingredients: edetate disodium (18.8 mg), polysorbate 80 (75 mg), lactose anhydrous (375 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment). Fosaprepitant dimeglumine hereafter will be referred to as fosaprepitant.

CLINICAL PHARMACOLOGY

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK1) receptor antagonist. Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion. Upon conversion of 188 mg of fosaprepitant dimeglumine (equivalent to 115 mg fosaprepitant free acid) to aprepitant, 18.3 mg of phosphoric acid and 73 mg of meglumine are liberated. Upon conversion of 245.3 mg of fosaprepitant dimeglumine (equivalent to 150 mg fosaprepitant free acid) to aprepitant, 23.9 mg of phosphoric acid and 95.3 mg of meglumine are liberated.

Mechanism of Action

 Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant.  Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

Current developer:    Merck & Co.

1: Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol. 2011 Apr 10;29(11):1495-501. Epub 2011 Mar 7. PubMed PMID: 21383291.

2: Marbury TC, Ngo PL, Shadle CR, Jin B, Panebianco D, Caro L, Valentine J, Murphy G. Pharmacokinetics of Oral Dexamethasone and Midazolam When Administered With Single-Dose Intravenous 150 mg Fosaprepitant in Healthy Adult Subjects. J Clin Pharmacol. 2011 Jan 5. [Epub ahead of print] PubMed PMID: 21209230.

3: Langford P, Chrisp P. Fosaprepitant and aprepitant: an update of the evidence for their place in the prevention of chemotherapy-induced nausea and vomiting. Core Evid. 2010 Oct 21;5:77-90. PubMed PMID: 21042544; PubMed Central PMCID: PMC2963924.

4: Colon-Gonzalez F, Kraft WK. Pharmacokinetic evaluation of fosaprepitant dimeglumine. Expert Opin Drug Metab Toxicol. 2010 Oct;6(10):1277-86. Review. PubMed PMID: 20795794; PubMed Central PMCID: PMC3155701.

5: Marbury TC, Jin B, Panebianco D, Murphy MG, Sun H, Evans JK, Han TH, Constanzer ML, Dru J, Shadle CR. Lack of effect of aprepitant or its prodrug fosaprepitant on QTc intervals in healthy subjects. Anesth Analg. 2009 Aug;109(2):418-25. PubMed PMID: 19608812.

6: Van Belle SJ, Cocquyt V. Fosaprepitant dimeglumine (MK-0517 or L-785,298), an intravenous neurokinin-1 antagonist for the prevention of chemotherapy induced nausea and vomiting. Expert Opin Pharmacother. 2008 Dec;9(18):3261-70. Review. PubMed PMID: 19040346.

7: Navari RM. Fosaprepitant: a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Rev Anticancer Ther. 2008 Nov;8(11):1733-42. Review. PubMed PMID: 18983233.

8: Olver IN. Prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant. Ther Clin Risk Manag. 2008 Apr;4(2):501-6. PubMed PMID: 18728837; PubMed Central PMCID: PMC2504061.

9: Navari RM. Fosaprepitant (MK-0517): a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Opin Investig Drugs. 2007 Dec;16(12):1977-85. Review. PubMed PMID: 18042005.

10: Lasseter KC, Gambale J, Jin B, Bergman A, Constanzer M, Dru J, Han TH, Majumdar A, Evans JK, Murphy MG. Tolerability of fosaprepitant and bioequivalency to aprepitant in healthy subjects. J Clin Pharmacol. 2007 Jul;47(7):834-40. Epub 2007 May 24. PubMed PMID: 17525168.