Fosaprepitant: a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is a distressing and common adverse event associated with cancer treatment. Updated antiemetic guidelines were published in 2008 by the National Comprehensive Cancer Network and, in 2006, by the American Society of Clinical Oncology, which have included the use of the new and more effective antiemetic agents 5-hydroxytryptamine-3 (5-HT3) receptor antagonist and neurokinin (NK)-1 receptor antagonist. Aprepitant is a selective NK-1 receptor antagonist approved as part of combination therapy with a corticosteroid and a 5-HT3 receptor antagonist for the prevention of acute and delayed CINV in patients receiving moderately and highly emetogenic chemotherapy. Fosaprepitant (also known as MK-0517 and L-758,298) is a water-soluble phosphoryl prodrug for aprepitant, which, when administered intravenously, is converted to aprepitant within 30 min of intravenous administration via the action of ubiquitous phosphatases. Owing to the rapid conversion of fosaprepitant to the active form (aprepitant), fosaprepitant 115 mg provided the same aprepitant exposure in terms of AUC as aprepitant 12 mg orally, and fosaprepitant is expected to provide a correspondingly similar antiemetic effect as aprepitant. Clinical studies have suggested that fosaprepitant could be appropriate as an intravenous alternative to the aprepitant oral capsule. In a study in healthy subjects, fosaprepitant 115 mg was generally well tolerated at a final drug concentration of 1 mg/ml, and fosaprepitant 115 mg was AUC bioequivalent to aprepitant 125 mg. Fosaprepitant in the dose of 115 mg has been approved by the US FDA, the EU and the Australian authorities on day 1 of a 3-day oral aprepitant regimen, with oral aprepitant administered on days 2 and 3. Fosaprepitant may be a useful parenteral alternative to oral aprepitant. Further study is needed to clarify the utility of fosaprepitant in the prevention of CINV and to clarify optimal dosing regimens that may be appropriate substitutes for oral aprepitant.