265121-04-8

Indications

Fosaprepitant dimeglumine is a new drug indicated to prevent nausea and vomiting associated with highly emetogenic cisplatin-based and moderately emetogenic cancer chemotherapy in adults.

Biological Activity

Fosaprepitant dimeglumine acts as a therapeutic agent to treat chemotherapy-induced nausea and vomiting. It also acts as a weak inhibitor of cytochrome P450 3A4 (CYP3A4).Fosaprepitant dimeglumine is a Substance P/neurokinin-1 (NK1) receptor antagonist. It is a water soluble prodrug of the antiemetic drug aprepitant.Fosaprepitant dimeglumine is a water-soluble prodrug form of the neurokinin-1 receptor antagonist aprepitant. Formulations containing fosaprepitant dimeglumine have been used to prevent chemotherapy-induced nausea and vomiting.

Side effects

Most common adverse reactions in adults (≥2%) are: fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, pain in extremity.Adverse reactions in pediatrics are similar to adults.

Mode 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 have shown 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.

Clinical claims and research

One of the most debilitating side effects of cancer treatment is CINV. Although concomitant anti-emetic agents have been prevalent for the past two decades, 50 60% of patients are still plagued by CINV. To meet this need, fosaprepitant dimeglumine has been launched as a water-soluble, phosphoryl pro-drug of aprepitant for intravenous applications. This pro-drug is rapidly converted to aprepitant in vivo, which has a high affinity for the NK-1 receptor (IC50= 90 50 pM for the displacement of [125I]-substance P from hNK-1 expressed in CHO cells); antagonism 606 Shridhar Hegde and Michelle Schmidt of NK-1 prevents binding of the endogenous substance P that is known to induce vomiting. Fosaprepitant is prepared by the regioselective phosphorylation of aprepitant with dibenzylphosphoryl chloride followed by catalytic hydrogenolysis in the presence of N-methyl-Dglucamine. It is approved for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly and moderately emetogenic cancer chemotherapy.

Definition

ChEBI: Fosaprepitant dimeglumine is an organoammonium salt obtained by reaction of fosaprepitant with two equivalents of 1-deoxy-1-(methylamino)-D-glucitol. A substance P/neurokinin 1 (NK1) receptor antagonist. 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 and postoperative nausea and vomiting It has a role as a prodrug, an antiemetic and a neurokinin-1 receptor antagonist. It contains a fosaprepitant(2-).

Brand name

IvEmend