EMEND(fosaprepitant dimeglumine)for Injection
DESCRIPTION
EMEND1 (fosaprepitant dimeglumine) for Injection is a sterile, lyophilized prodrug of aprepitant 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) and its structural formula is:
Fosaprepitant dimeglumine is a white to off-white amorphous powder with a molecular weight of 1004.83. It is freely soluble in water.
EMEND for Injection is a lyophilized prodrug of aprepitant containing polysorbate 80 (PS80), to be administered intravenously as an infusion.
Each vial of EMEND for Injection for intravenous administration contains 188 mg of fosaprepitant dimeglumine equivalent to 115 mg of fosaprepitant 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). Fosaprepitant dimeglumine hereafter will be referred to as fosaprepitant.
Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist, chemically described as 5-[[(2R,3S )-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.
Its empirical formula is C23H21F7N4O3, and its structural formula is:
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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 (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Upon conversion of 115 mg of fosaprepitant to aprepitant, 18.3 mg of phosphate and 73 mg of meglumine are liberated from fosaprepitant.
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.
Pharmacokinetics
Aprepitant after Fosaprepitant Administration
Following a single intravenous dose of fosaprepitant administered as a 15-minute infusion to healthy volunteers the mean AUC0-∞ of aprepitant was