Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics

Abstract

The advent of the 5HT 3 receptor antagonists (5HT 3 antagonists) in the 1990 s and the combination with dexamethasone has resulted in acute emesis protection in 70% of patients receiving highly emetogenic chemotherapy. Despite complete protection in the acute phase, however, 40% of patients as yet have symptoms in the delayed phase. 5HT 3 antagonists and dexamethasone are only modestly effective in this delayed phase. Moreover, the antiemetic protection over repeated cycles is not sustained. Neurokinine 1 receptor antagonists (NK 1 antagonists) belong to a new class of antiemetic agents that specifically target the NK 1 receptor, which is involved in both the acute and, particularly, the delayed phase of emesis. Clinical studies have demonstrated that the addition of NK 1 antagonists to dual therapy with a 5HT 3 antagonist plus dexamethasone improves the acute emesis protection by a further 10 -15%. In the delayed phase, the proportion of patients remaining free of emesis increases by even 20 -30%. Since the effectiveness of this triplet combination was found to be sustained over six cycles of chemotherapy, the chance for an individual patient to remain completely protected during both the acute and the delayed phase over six chemotherapy cycles is nearly doubled. Keywords: Antiemetics; 5HT 3 antagonists; NK 1 antagonists; neurokinine receptor antagonists; substance P Nausea and vomiting are considered as two of the most distressing side effects of anticancer chemotherapy. Chemotherapy-induced emesis has a serious impact on a patient's quality of life and the possibility to complete the planned chemotherapy successfully. Cisplatin is most commonly associated with profound nausea and vomiting, which follows a distinct pattern of an acute phase (0 -24 h after the start of chemotherapy) and a delayed phase that is mostly defined as occurring on days 2 -5 after the chemotherapy. Since severe emesis occurs in virtually all patients who receive a cisplatin dose of X50 mg m À2 , cisplatin-induced nausea and vomiting has served as the model to test anti-emetic agents for highly emetogenic chemotherapy Gralla et al, 1999). CURRENT ROLE OF 5HT 3 ANTAGONISTS PLUS DEXAMETHASONE; ACUTE PHASEBefore the advent of the 5HT 3 antagonists, nausea and vomiting were ranked as the two most distressing side effects of systemic chemotherapy (Coates et al, 1983). The use of 5HT 3 antagonists (ondansetron, granisetron and tropisetron) has provided complete acute emesis protection in 50-70% of patients receiving a first cycle of cisplatin-based chemotherapy . The addition of dexamethasone to 5HT 3 antagonists has improved the complete protection rate by a further 10 -15%, resulting in a total complete acute emesis protection in 65 -80% of patients .

Effectiveness of a single-day three-drug regimen of dexamethasone, palonosetron, and aprepitant for the prevention of acute and delayed nausea and vomiting caused by moderately emetogenic chemotherapy

“…Second, it is necessary to have appropriate remedies to address the problem. The development of serotonin antagonists, recognition of the antiemetic properties of corticosteroids, and recent development of the NK-1 antagonists, has markedly improved management of this problem [8,35]. However, new strategies continue to be required for delayed vomiting, where complete response rates have lagged behind acute complete response rates even if appropriate guidelines are followed [6].…”

Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications

“…Following prophylactic treatment with 4 mg of ondansetron, genetically defined UMs (patients with three copies of the CYP2D6 gene) experienced significantly higher incidences of postoperative vomiting than PMs, IMs, or EMs (5 of 11 patients, 45%; p < .01). Genetic variation has also been suggested as a potential explanation for the finding that patients refractory to treatment with ondansetron experience emetic protection with granisetron [67,68]. Conversely, PM patients receiving 5-HT 3 -receptor antagonists metabolized by CYP2D6 are likely to have higher serum concentrations of these agents [63], which may prolong the duration of drug effect, but may also increase the duration of drug-induced adverse events and increase the potential for drug-drug interactions.…”

5‐hydroxytryptamine type‐3 receptor antagonists for chemotherapy‐induced and radiotherapy‐induced nausea and emesis

“…44,46 A further rationale that recently was proposed for the efficacy of granisetron in patients who were refractory to ondansetron therapy may be the issue of genetic polymorphism of the CYP2D6 enzyme. 81 Recent data suggest that those patients who are ultrarapid metabolizers of CYP2D6 substrates are at risk of developing severe acute CINV after moderately to highly emetogenic chemotherapy regimens, despite treatment with ondansetron. 39 Ondansetron is metabolized partially by CYP2D6 in addition to CYP3A4, CYP1A1, and CYP1A2; whereas granisetron is metabolized principally by CYP3A4.…”