Use For Neurokinin Antagonists

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ABSTRACT

Background

In early clinical trials with patients obtaining highly emetogenic chemotherapy, the neurokinin antagonist aprepitant considerably enhanced the efficacy of a benchmark antiemetic regimen comprising of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study will be performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV).

Methods

Patients receiving cisplatin = 70 mg/m2 for the first time will be given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients will be recorded nausea and vomiting episodes in a diary. The primary end point will complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons will be made using logistic regression models. Tolerability will be assessed by reported adverse events and physical and laboratory assessments.

Results

The patients with complete response on days 1 to 5 will significantly be higher in the aprepitant group, as will be on day 1, and especially on days 2 to 5 (P < .001 for all three comparisons). Compared with standard dual therapy, addition of aprepitant is generally well tolerated and provides consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy.

INTRODUCTION

NAUSEA AND vomiting are amidst the most dreaded and distressing harmful effects of chemotherapy from a patient's standpoint. Substantial progress has been made in improving the control of chemotherapy-induced nausea and vomiting (CINV) due in large part to the introduction of selective type-three 5-hydroxytryptamine (5-HT3) receptor antagonists (RAs) approximately 10 years ago.4 Nevertheless, CINV remains suboptimally controlled for a significant number of cancer patients receiving chemotherapy. Remaining trials encompass symptoms occurring more than 24 hours after chemotherapy (delayed CINV), symptoms throughout replicate cycles of chemotherapy, and symptoms associated with very high-dose chemotherapy. Significant advancement in stopping CINV is expected to depend on the introduction of new and effective antiemetic agents. 1

Substance P is a regulatory peptide discovered in localities of the CNS (including the nucleus tractus solitarii and locality postrema) and the gastrointestinal tract (vagal afferents) believed to be essential constituents of the emetic reflex. The actions of substance P are mediated through the neurokinin-1 (NK1) receptor, a G-protein receptor coupled to the inositol phosphate signal transduction pathway. In animal models, selective nonpeptide antagonists of the NK1 receptor have demonstrated antiemetic activity against central, peripheral, and combined emetic stimuli. Penetration of these agencies into the CNS seems to be absolutely vital to their antiemetic action.

Aprepitant (EMENDTM; Merck and Co Inc, Whitehouse Station, NJ) represents a new class of antiemetic. It is a potent, selective, CNS-penetrant, oral nonpeptide antagonist of the NK1 receptor. In the same preclinical models used to predict the clinical utility of the 5-HT3 RAs, selective NK1 RAs have also demonstrated potent ability to inhibit emesis induced by ...