Management of acute and delayed chemotherapy-induced nausea and vomiting: role of netupitant–palonosetron combination

Abstract

PurposeThe purpose of this review is to summarize and discuss the recently published data (both original studies and reviews) on the oral medication NEPA, consisting of netupitant (a neurokinin-1 receptor antagonist [NK1RA], 300 mg dose) and palonosetron (5-hydroxytryptamine [serotonin or 5HT] type 3 receptor antagonist [5HT3RA], 0.5 mg dose), in the prevention of the acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy.MethodsThis review was based on the very limited number of available published trials consisting of two Phase III studies and one Phase II dose-selecting trial.ResultsThese studies demonstrated some therapeutic benefits of NEPA over related chemotherapy-induced nausea and vomiting (CINV) prophylaxis management, as well as its beneficial safety profile. In particular, compared with single-dose 0.5 mg palonosetron, the complete response rates for all phases of CINV for the first cycle of highly emetogenic chemotherapy (with cisplatin), as well as anthracycline–cyclophosphamide-based moderately emetogenic chemotherapy, were significantly higher for single-dose NEPA. The high efficacy of NEPA in terms of prevention of CINV continued throughout repeated cycles of highly and moderately emetogenic therapies.ConclusionIt is currently recommended that patients who are administered highly emetogenic chemotherapy regimens should obtain a three-drug combination consisting of NK1RA, 5HT3RA, and dexamethasone. The recently available oral combination of NEPA plus dexamethasone provides an additional pharmacological management option that could be considered in this scenario.

Role of Calcium in Vomiting

“…However, our more recent findings suggest that 5-HT and substance P are concomitantly involved in both emetic phases in the gastrointestinal tract as well as in the brainstem [2,16]. While netupitant is a highly selective and a longer-acting second generation NK 1 R antagonist, palonosetron is considered as a second generation 5-HT 3 R antagonist with a unique antiemetic profile in both humans [79,80] and the least shrew model of emesis [45]. A successful regimen of an oral fixed combined dose of netupitant/palonosetron (NEPA) (Figure 2) has been formulated with over 85% clinical efficacy, good tolerability, and high central nervous system penetrance for the prophylactic treatment of acute and delayed chemotherapy-induced nausea and vomiting in cancer patients receiving chemotherapy [9,81,82].…”

“…Studies using Ca 2+ imaging performed in vitro in the brainstem slice preparation suggest that emetic agents evoke direct excitatory effects on cytosolic Ca 2+ signals in vagal afferent terminals in the nucleus tractus solitarius which potentiate local neurotransmitter release [5,14,15]. Therefore, chemotherapeutics including cisplatin seem to activate emetic circuits through a number of neurotransmitters released in a Ca 2+ -dependent (1) Netupitant and palonosetron are highly selective respective antagonists of NK 1 Rs and 5-HT 3 Rs are approved to treat the acute-and delayed-phases of chemotherapy-induced nausea and vomiting (CINV) in cancer patients [79][80][81][82]. Our studies [83][84][85][86] indicate that suppression of Ca 2+ signaling is involved in antiemetic efficacy of both palonosetron and netupitant.…”

Newest Drugs for Chronic Unexplained Nausea and Vomiting

“…Netupitant is potent, highly penetrant into the brain, and has a 90 hour half life versus 9–13 hours for aprepitant (27, 28). Netupitant and palonosetron have additive effects on inhibiting 5-HT 3 and NK 1 receptor crosstalk, enhancing antiemetic effects of this combination (29).…”

“…Netupitant and palonosetron have additive effects on inhibiting 5-HT 3 and NK 1 receptor crosstalk, enhancing antiemetic effects of this combination (29). In a phase 2 trial and in two phase 3 investigations, this agent produced superior rates of complete response of acute and delayed CINV for 120 hours compared to palonosetron given alone and to 3 days of a combination of aprepitant and ondansetron (27, 30, 31, 32). Benefits were maintained over repeated courses and were associated with improved quality of life (31, 32).…”

Chemotherapy Induced Nausea and Vomiting;

“…2,[4][5][6] Therefore, this area needs to be explored further addition of drugs like antipsychotics (olanzapine) or NK1 receptor antagonist aprepitant, fosaprepitant, netupitant (with palonosetron or rolapitant) to the standard regimen, can be donein this regard to provide a better control. 7,8 Also, agents like benzodiazipines, cannabinoids, haloperidol etc hasbeen usedto control breakthrough vomiting. [9][10][11][12] But in adeveloping countries like Pakistan,all these drugs are either not available or are very costly and a common man can not afford it.So they are not routinely prescribed as prophylaxis against CINV.…”