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Pharmacology Update: Aprepitant Capsules (Emend—Merck & Co)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA has approved aprepitant for preventing both acute and delayed nausea and vomiting associated with chemotherapy. Aprepitant is a unique antiemetic, the first selective antagonist of the neurokinin-1 (NK-1) receptor, and the first to be approved for acute and delayed nausea and vomiting. Merck & Co markets aprepitant capsules as "Emend."
Aprepitant is indicated, in combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.1
Aprepitant is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose is 125 mg orally 1 hour prior to chemotherapy on day 1 and 80 mg in the morning on day 2 and day 3.1 Based on clinical studies, the recommended dose of dexamethasone is 12 mg orally on day 1 and 8 mg orally on day 2, 3, and 4. The recommended dose of ondansetron is 32 mg IV on day 1.
Aprepitant is available as 80-mg and 125-mg capsules.
Aprepitant is the first drug to be approved for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. The combination of aprepitant 125 mg orally, dexamethasone 12 mg orally, and ondansetron 32 mg IV on day 1 and aprepitant 80 mg orally and dexamethasone 8 mg in the morning on days 2 and 3 was reported to be more effective than dexamethasone 20 mg orally and ondansetron 32 mg IV on day 1 and dexamethasone 8 mg morning and evening on days 2 and 3.1 The percent of patients with complete response (no emetic episodes and no use of rescue therapy) in the acute phase (0-24 hrs) ranged from 83-89% for the aprepitant regimen compared to 68-75% for the standard regimen (P < .001). For the delayed phase (25 -120 h), complete response ranged from 68-75% for aprepitant and 47-56% (P < .001) for the standard regimen.
The combination of aprepitant and dexamethasone appears to be less effective than a 5-HT3 and dexamethasone combination in acute nausea and vomiting.2 Aprepitant is a substrate, moderate inhibitor, and inducer of CYP3A4 inhibitor and may affect drug plasma levels of drug metabolized by this isoenzyme.1 Drugs that inhibit or are inducers of this isoenzyme may affect the metabolism of aprepitant. Aprepitant is also an inducer of CYP2C9. The oral dose of dexamethasone or methylprednisone should be administered at about 50% of the dose normally given without aprepitant. Intravenous methylprednisolone should be given at about 25% of the usual dose.
Aprepitant is the first of the neurokinin-1 (NK-1) receptor antagonists. Substance P is the neurokinin neurotransmitter that selectively binds to NK-1.3 In animal models, substance P has been found to produce emesis, and NK-1 receptor antagonists show antiemetic activity.4 When aprepitant is added to a "standard" regimen of a 5-HT3 receptor antagonist and dexamethasone, both acute and delayed phase nausea and vomiting were reduced. FDA approval was based on 2 studies involving a total of 1105 patients who received cisplatin and other chemotherapeutic agents (eg, etoposide, fluorouracil, gemcitabine, vinorelbine, paclitaxel).1 In both studies, a statistically significantly higher proportion of patients with added aprepitant had better outcomes overall, in the acute phase and delayed phase. The primary end point was no emesis and no rescue therapy (complete response). Aprepitant appears to be well tolerated although drug interactions, involving primarily CYP3A4 and CYP2C9, are a possibility.
The wholesale cost for a course of aprepitant (1 ´ 125 mg and 2 ´ 80 mg) is $250.
Acute and delayed nausea and vomiting commonly occur with the administration of cisplatin, carboplatin, cyclophosphamide, or doxorubicin. Cisplatin is one of the most emetogenic drugs at doses of 50 mg/m2 or higher. Antiemetic prophylaxis with a 5-HT3 receptor antagonist in combination with a corticosteroid is standard therapy in these patients.5 However, this combination is not as effective in preventing delayed nausea and vomiting, and approximately 50% of patients will suffer delayed nausea and vomiting. The addition of aprepitant appears to reduce the incidence of delayed nausea and vomiting compared to the 2-drug combination. In addition, the 3-drug regimens also appeared to reduce the incidence of acute nausea and vomiting compared to the 2-drug combination. This is particularly significant as poor control of acute nausea and vomiting has been reported as an important predictor of delayed nausea and vomiting.6,7 Whether the combination of a neurokinin-1 receptor antagonist, 5-HT3 receptor antagonist, and a corticosteroid will become the standard of care will be determined with broader clinical experience.
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
1. Emend Product Information. Merck & Co, Inc. March 2003.
2. Campos D. et al. J Clin Oncol. 2001;19:1759-1767.
3. Bleiberg H. Curr Opin Oncol. 2000;12(4):284-288.
4. Tattersall FD, et al. Neuropharmacology. 1996;35: 1121-1129.
5. ASHP Reports. ASHP. 1999;56(8):729-764.
6. Mantovani G, et al. Oncol Rep. 1998;5(1):273-280.
7. Schnell FM. The Oncologist. 2003;8:187-198.