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

REVIEW Prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant Ian N Olver The Cancer Council Australia, Sydney, New South Wales, Australia 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. Keywords: fosaprepitant, aprepitant, neurokinin1 receptor, emesis, chemotherapy Introduction Correspondence: Ian Olver Clinical Professor, Department Medicine, University of Sydney), C/O The Cancer Council Australia, 120 Chalmers Street, Surry Hills, New South Wales, Australia 2010, GPO Box 4708, Sydney NSW 2001 Tel +61 2 8063 4100 Fax +61 2 8063 4102 Email The introduction of cytotoxic chemotherapy, and particularly cisplatin, was associated with nausea and vomiting that did not respond to conventional doses of the then available antiemetics, exemplified by metoclopramide and prochlorperazine. Of the factors that predicted nausea and vomiting the most significant was the cytotoxic drug, as each drug displayed a different emetic potential, and there were different mechanisms by which the cytotoxics could cause vomiting (Andrews et al 1998; Hesketh 1999). The most common pattern of nausea and vomiting is acute emesis which commences within hours of receiving chemotherapy and lasts over the first 24 hours. This can be followed by delayed emesis commencing near the beginning of the first day and often lasting for at least 5 days (Kris et al 1985). Those patients who experience severe postchemotherapy emesis are then prone to developing anticipatory emesis as a conditioned response (Morrow 1982). Patients who have poor control of post chemotherapy emesis also demonstrate deterioration in their quality of life (Osoba et al 1997). It was the discovery that two important mechanisms for post-chemotherapy emesis were mediated through 5 hydroxytryptamine3 (5HT3) and neurokinin1 (NK1) receptors and the development of antagonists that saw a great impact made upon the control of chemotherapy-induced vomiting and to a lesser extent nausea. The 5HT3 receptors, predominantly in the small bowel, were major mediators of acute emesis, and the first of the antagonists, ondansetron, when given prior to chemotherapy, revolutionized the control of post chemotherapy acute emesis. Ondansetron and dexamethasone controlled acute emesis in over 80% patients (Gralla et al 1999). Patients, however, were still Therapeutics and Clinical Risk Management 2008:4(2) 501–506 © 2008 Dove Medical Press Limited. All rights reserved 501 Olver listing nausea and vomiting in their top three side effects even after the great improvement in the control of acute emesis (Boer-Dennert et al 1997). This was due to the incidence of delayed emesis which can occur in 20%–25% patients in the absence of acute emesis, and which was being underestimated by clinicians by up to 30% (Grunberg et al 2004). Unfortunately, in only 50% patients was the delayed phase of emesis, caused by drugs such as cisplatin, controlled by ondansetron and dexamethasone. It was the dexamethasone that was the most active drug, suggesting that a different mechanism was responsible for delayed compared with acute emesis (Olver et al 1996). Substance P, a tachykinin, binds to NK1 receptors in the brain stem which send messages to the vomiting center and induce vomiting. Blocking the NK1 receptor lessens vomiting after cisplatin, and a variety of other emetic stimuli (Diemunsch and Grelot 2000). With the development of the orally active NK1 receptor antagonist, aprepitant, it was found that when it was added to ondansetron and dexamethasone it improved the control of cisplatin-induced acute emesis, but when continued for 2 further days had a major impact on the control of the delayed phase of the post-chemotherapy emesis (Hesketh et al 2003; Poli-Bigelli et al 2003). Fosaprepitant (L-758,298 or MK-0517) is a prodrug of aprepitant that can be administered intravenously and is converted into aprepitant within 30 minutes (Navari 2007). The pharmacology of fosaprepitant Fosaprepitant dimeglumine is a white powder which is freely water soluble and is a phosphoryl prodrug of aprepitant (Hale et al 2000). Its antiemetic properties are attributable to aprepitant, which is a selective neurokinin 1 (NK1) receptor antagonist with low affinity for NK2 and NK3 receptors (Watson et al 1998). It inhibits chemotherapy emesis by penetrating the brain and occupying central NK1 receptors for a sufficient duration to inhibit both the acute and delayed phases of emesis (Tattersall et al 2000). Antiemetic efficacy with aprepitant increases with receptor occupancy up until a dose of 125 mg orally, but there is no greater benefit with higher doses (Hargreaves 2002). Fosaprepitant 115 mg given intravenously is bioequivalent to aprepitant 125 mg given by mouth with similar plasma concentrations at 24 hours (Merck and Co Inc 2007). It has been trialed in single daily doses for up to 4 days. Fosaprepitant is converted to aprepitant within 30 minutes after the end of an infusion. Aprepitant is 95% bound to plasma proteins. In vitro studies show that aprepitant is metabolized 502 in the liver primarily by CYP3A4, with minor metabolism by CYP1A2 and CYP2C19. Preclinical toxicology studies of bolus fosaprepitant administered in seconds to dogs and rats showed that concentrations of
1 mg/mL were well tolerated. Concentrations up to 25 mg/ml at low doses (2–4 mg/kg/day) were well tolerated in dogs but intermediate concentrations (10 mg/mL) given at higher doses (32 mg/kg/day) caused venous irritation (Lasseter et al 2007). There have been seven metabolites identified in human plasma, which are only mildly active. Following a single intravenous dose of 14C-labeled fosa (...truncated)