Current Trends and Future Directions in the Management of Delayed Nausea and Vomiting

European Oncology & Haematology, 2013;9(2):84–9

Abstract:

The prophylaxis of chemotherapy-induced nausea and vomiting benefited greatly from the introduction of neurokinin-1 (NK1) receptor antagonists (RAs). Current emesis guidelines recommend that NK1 receptor antagonists be combined with 5-HT3 receptor antagonists and dexamethasone for highly emetic chemotherapy and moderately emetic chemotherapy. The first such medication, aprepitant, was approved in the US in 2003. Fosaprepitant, an intravenous prodrug of aprepitant, is also available as a single dose on day 1 in combination with other antiemetics. Fosaprepitant is rapidly converted to the active aprepitant and exhibits a similar half-life to orally administeredaprepitant. In addition, receptor-binding studies have shown aprepitant striatal NK1 receptor occupancy of 90 % for over 48 hours after exposure. These characteristics may allow aprepitant, fosaprepitant and the newer NK1 RAs to be administered in a single dose on day 1. Olanzapine may prove to be a novel approach in the treatment of CINV, particularly in the management of nausea.
Keywords: Chemotherapy-induced nausea and vomiting, aprepitant, neurokinin-1 receptor antagonist, antiemetic, aprepitant, casopitant, fosaprepitant
Disclosure: The authors have no conflicts of interest to declare.
Received: September 20, 2013 Accepted October 21, 2013 Citation European Oncology & Haematology, 2013;9(2):84–9
Correspondence: Bernardo L Rapoport, The Medical Oncology Centre of Rosebank, 129 Oxford Road, Saxonwold 2196, Johannesburg, PO Box 2040, Parklands 2121, South Africa. E: brapoport@icon.co.za

An erratum to this article can be found below.

Over the last 10 years, the availability of neurokinin-1 receptor antagonists (NK1 RAs) has led to marked improvements in the treatment of chemotherapy-induced nausea and vomiting (CINV).

In clinical trials with the NK1 RA aprepitant in combination with ondansetron and dexamethasone (DEX), more than 70 % of patients treated with highly emetic chemotherapy (HEC), such as cisplatinbased regimens, achieved overall complete response (CR) (no vomiting, no rescue medication during the overall phase).1,2 Warr et al. showed that women receiving anthracycline and cyclophosphamide (AC)-based moderately emetic chemotherapy (MEC), patients receiving a 3-drug antiemetic regimen with aprepitant had overall CR rates over 50 % compared with 42.5 % with a two-drug antiemetic regimen without an NK1 RA (p=0.015).3 Similar outcomes were demonstrated in a study by Rapoport et al.4 The demonstrated advantage of adding a NK1 RA to antiemetic regimens has led to its inclusion as an essential component in CINV prophylaxis guidelines, in combination with a 5-HT3 RA and DEX.5–7

Aprepitant was initially approved by the US Food and Drug Administration (FDA) in 2003 for the treatment of CINV in combination with other antiemetic agents. It is currently administered as 3 doses taken orally: 125 mg before chemotherapy on day 1, and 80 mg on days 2 and 3.1–3 Fosaprepitant is a prodrug of aprepitant that is readily and rapidly converted to aprepitant via phosphatase enzymes in the bloodstream. Fosaprepitant is available as an intravenous (IV) formulation that can be used in place of the oral dose of aprepitant on day 1. It may be particularly advantageous in patients who cannot accept or tolerate an oral formulation.

A phase III study with another NK1 RA, casopitant, was completed for treatment of CINV in both 3- and 1-day dosing schedules. In July 2008, GlaxoSmithKline (GSK) filed a marketing authorisation application with the European Medicines Agency. The application was withdrawn in September 2009 because GSK decided that further safety assessment was necessary, and that it would take considerable time to produce these data. Nevertheless, the potential convenience of administering dosing the NK1 RA in the clinic without having to prescribe additional NK1 doses for patients to take home was of substantial interest to oncologists.

Other NK1 RAs are in phase III clinical development for CINV, including rolapitant and netupitant (NETU).8,9 Rolapitant is a potent, selective NK1 RA that is rapidly absorbed, has a remarkably long half-life (up to 180 hours) and appears to have a low potential for drug–drug interactions. Rolapitant has been free of clinically significant drug interactions in studies conducted to date. Specifically, it does not alter the pharmacokinetics of midazolam or other CYP3A4 substrates and, consequently, is unlikely to have an effect on the pharmacokinetics of drugs metabolised by cytochrome P450 3A4. Therefore, administration of rolapitant is unlikely to cause a clinically significant pharmacokinetic interaction with many commonly used drugs intended for cancer patients undergoing chemotherapy.10NETU is a potent and selective NK1 RA under development in combination with a fixed dose of palonosetron (PALO) for the prevention of CINV. NEPA, a fixed-dose combination of NETU – a new NK1 RA – and PALO – a pharmacologically distinct 5-HT3 RA – targets these dual antiemetic pathways and has been shown to uniquely work synergistically in vitro.9

Other NK1 RA, such as vestipitant, have been under investigation for other indications (e.g. tinnitus).11 Olanzapine is a thienobenzodiazepine that can act on multiple receptors including dopamine (D1, D2, D3, D4) and the serotonin receptors (5HT2a, 5HT2c, 5HT3, 5HT6) as well as adrenergic, muscarinic and histamine receptors.12 Common side effects are weight gain, sedation and impaired glucose tolerance. Its major use is as an oral antipsychotic agent. It has been found to be active in the prevention of both acute and delayed emesis in early phase trials, with chemotherapy of high emetic potential including cisplatin, and chemotherapy of moderate emetic potential including cyclophosphamide, doxorubicin or irinotecan.

Neurokinin-1 Inhibitor Clinical Pharmacology
Most of the current published NK1 clinical pharmacology literature is with the use of aprepitant. Both substance P and serotonin (5-HT3) have been implicated in CINV by triggering the corresponding receptors in the brain and in the gastrointestinal tissues, respectively.13 Substance P and 5-HT3 are generally thought to have different time courses of action due to the biphasic nature of cisplatin-based HEC;14,15 the 5-HT3- mediated effect occurs within a few hours of the administration of chemotherapy, early in the acute phase. The NK1-mediated effect starts at approximately 15 hours following chemotherapy, and continues into the delayed phase.15,16

While the 5-HT3 mediated phase is quite short and essentially complete in the first 24 hours after chemotherapy, the substance P/NK1-mediated phase in HEC extends for 60 or more hours postchemotherapy. 17,18 The acute phase of chemotherapy has been defined as the first 24 hours post-chemotherapy, and the delayed phase as any time in the 96 hours after that. These phase definitions are rooted in the need for readily measurable endpoints, rather than the biological phases associated with 5-HT3 and NK1. However, the 5-HT3 RA and NK1 RA are often associated with acute and delayed CINV, respectively. However, it is clear that the NK1 mediated effect spans both phases in HEC.17,19 AC-based MEC on the other hand is monophasic, with both the 5-HT3 and NK1-mediated effects occurring within a few hours after chemotherapy, early in the acute phase.15 When the same effects are evaluated in patients receiving AC-based MEC, aprepitant was effective earlier in the acute phase – starting as early as 6 hours post-chemotherapy – compared with approximately 18 hours in HEC studies.15,17 In a Kaplan-Meier analysis of time to first emesis in HEC studies, the curves representing the regimen with aprepitant and active control were clearly separated as early as 15 hours.15,17 This highlights the differential time course of action of 5-HT3 and NK1 RAs when used with HEC and MEC.15 Hence NK1 RAs, although often associated primarily with the delayed phase, also have a critical role during the acute phase in both HEC and MEC as it was shown in the registration trials.

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Keywords: Chemotherapy-induced nausea and vomiting, aprepitant, neurokinin-1 receptor antagonist, antiemetic, aprepitant, casopitant, fosaprepitant