Prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant

Abstract

Fosaprepitant is a prodrug of aprepitant, a neurokinin1 (NK1) receptor antagonist used in prophylactic antiemetic regimens used prior to cytotoxic chemotherapy. Fosaprepitant is being developed to provide a parenterally administered alternative to the orally administered aprepitant. Fosaprepitant is rapidly converted to aprepitant and an intravenous dose of 115 mg is bioequivalent to 125 mg orally, with similar plasma concentrations at 24 hours. In phase I and II trials fosaprepitant shows efficacy, but the large randomized efficacy studies have utilized aprepitant. When it is added to dexamethasone and a 5HT3 receptor antagonist on day 1 prior to chemotherapy aprepitant improves the control of acute post chemotherapy emesis and when continued on days 2 and 3 with dexamethasone it demonstrated even greater improvement in the control of delayed emesis. This has been shown with both cisplatin-containing regimens and those based upon cyclophosphamide and an anthracycline. Fosaprepitant is well tolerated with mild to moderate venous irritation being the only additional toxicity to those seen with oral aprepitant, and that is a function of dose, concentration, and infusion rate. Headaches are the other toxicity most commonly reported. Fosaprepitant can be used as a parenteral alternative to aprepitant in regimens to control chemotherapy-induced emesis.

Management of chemotherapy-induced nausea and vomiting

“…Fosaprepitant dimeglumine (MK-0517 or L-758,298), a prodrug of aprepitant, was developed to provide a parenteral alternative to the orally administered aprepitant (19,20). Fosaprepitant is rapidly converted to aprepitant via the action of ubiquitous phosphatases.…”

Results of a 7-day aprepitant schedule for the prevention of nausea and vomiting in 5-day cisplatin-based germ cell tumor chemotherapy

“…There are also data from studies of casopitant, an NK 1 receptor antagonist now withdrawn due to its toxicity, that larger doses of the NK 1 receptor antagonist given on day 1 may preclude the need for days 2 and 3 dosing [19]. There is also the possibility of intravenous dosing of the NK 1 receptor antagonist using fosaprepitant [20], or use of the novel NK 1 receptor antagonist netupitant.…”

Pharmacogenomics in cancer supportive care: key issues and future directions

“…Aprepitant, or its intravenous formulation fosaprepitant, is a moderate inhibitor of CYP3A4. This increases the AUC of dexamethasone 2.2-fold, which means that with concomitant use, the dose of dexamethasone should be halved to reduce dexamethasone toxicity [33]. There is no clinically important interaction reported with ondansetron.…”

“…Drugs potentially used concomitantly with cancer therapy, which are strong CYP3A4 inducers, include rifampicin and unorthodox therapies such as St John's Wort, which will reduce the concentration of aprepitant, whereas strong inhibitors such as ketoconazole can increase the AUC of aprepitant up to fivefold. Aprepitant also induces the metabolism of drugs metabolized by CYP2C9 which requires careful monitoring of drugs such as warfarin, phenytoin, and tolbutamide [33,34].…”