BACKGROUND
The neurokinin‐1 antagonist aprepitant (EMEND™; Merck Research Laboratories, West Point, PA) has been shown to reduce chemotherapy‐induced nausea and vomiting when it is given with a 5‐hydroxytryptamine‐3 receptor antagonist and dexamethasone. The current study sought to define the most appropriate dose regimen of oral aprepitant.
METHODS
This multicenter, randomized, double‐blind, placebo‐controlled study was conducted in patients with cancer who were receiving initial cisplatin (≥ 70mg/m2) and standard antiemetic therapy (intravenous ondansetron plus oral dexamethasone). Patients were randomized to receive standard therapy plus either aprepitant 375 mg on Day 1 and 250 mg on Days 2–5, aprepitant 125 mg on Day 1 and 80 mg on Days 2–5, or placebo. Due to an apparent interaction with dexamethasone suggested by pharmacokinetic data obtained while the study was ongoing, the aprepitant 375/250 mg dose was discontinued and replaced with aprepitant 40 mg on Day 1 and 25 mg on Days 2–5, and a new randomization schedule was generated. Patients recorded nausea and emesis in a diary. The primary endpoint was complete response (no emesis and no rescue therapy), which was analyzed using an intent‐to‐treat approach with data obtained after the dose adjustment. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments, and included all available data.
RESULTS
The percentages of patients who achieved a complete response in the overall study period were 71.0% for the aprepitant 125/80‐mg group (n = 131 patients), 58.8% for the aprepitant 40/25‐mg group (n = 119 patients), and 43.7% for the standard therapy group (n = 126 patients; P < 0.05 for either aprepitant regimen vs. standard therapy). Rates for Day 1 were 83.2% for the aprepitant 125/80‐mg group, 75.6% for aprepitant 40/25‐mg group, and 71.4% for the standard therapy group (P < 0.05 for aprepitant 125/80 mg vs. standard therapy), and rates on Days 2–5 were 72.7% for the aprepitant 125/80‐mg group, 63.9% for the aprepitant 40/25‐mg group, and 45.2% for the standard therapy group (P < 0.01 for either aprepitant group vs. standard therapy). The efficacy of the aprepitant 375/250‐mg regimen was similar to that of the aprepitant 125/80‐mg regimen. The overall incidence of adverse events was generally similar across treatment groups: 85% in the aprepitant 375/250‐mg group (n = 34 patients), 76% in the aprepitant 125/80‐mg group (n = 214 patients), 71% in the aprepitant 40/25‐mg group (n = 120 patients), and 72% in the standard therapy group (n = 212 patients), with the exception of a higher incidence of infection in the aprepitant 125/80‐mg group (13%) compared with the standard therapy group (4%).
CONCLUSIONS
When it was added to a standard regimen of intravenous ondansetron and oral dexamethasone in the current study, aprepitant reduced chemotherapy‐induced nausea and vomiting and was generally well tolerated, although increases in infection were noted that...
In early clinical trials, the NK(1) receptor antagonist, aprepitant (EMEND(R)) was shown to improve the protection provided by the best available therapy (hereafter referred to as 'standard therapy': a 5-HT(3) receptor antagonist and dexamethasone) against chemotherapy-induced nausea and vomiting over multiple cycles of cisplatin-based chemotherapy. To further study the sustainment of antiemetic efficacy of aprepitant plus standard therapy over more than one cycle of chemotherapy, we examined combined data from the multiple cycles extensions of two phase III clinical trials of oral aprepitant plus standard therapy for the prevention of chemotherapy-induced nausea and vomiting. Data were pooled from two multicentre, randomised, double-blind, placebo-controlled studies with identical design and treatment regimens. Cancer patients receiving a first cycle of cisplatin-based (>or=70 mg/m(2)) chemotherapy were randomised to one of two treatment groups as follows: the standard therapy group received ondansetron 32 mg intravenously (i.v.) and dexamethasone 20 mg on day 1 and dexamethasone 8 mg twice daily (b.i.d.) on days 2-4. The aprepitant group received aprepitant 125 mg, ondansetron 32 mg i.v., and dexamethasone 12 mg on day 1, aprepitant 80 mg and dexamethasone 8 mg on days 2-3, and dexamethasone 8 mg on day 4. Patients had the option to receive the same blinded treatment for up to five additional cycles. The analysis used a combined exploratory endpoint of no emesis and no significant nausea (i.e. nausea which interfered with a patient's normal activities) over the 5 days following cisplatin, for up to six cycles of chemotherapy. A cumulative probabilities approach incorporating a model for transitional probabilities was used to analyse the data. Tolerability was assessed by reported adverse events and physical and laboratory assessments. Baseline characteristics, reasons for discontinuation, and drop-out rates were similar between groups. In every cycle, the estimated probabilities (rates) of no emesis and no significant nausea were significantly higher (P<0.006) in the aprepitant group: in the first cycle, rates were 61% in the aprepitant group (N=516) and 46% in the standard therapy group (N=522), and thereafter, rates for the aprepitant regimen remained higher throughout (59% (N=89) versus 40% (N=78) for the standard therapy, by cycle 6). Repeated dosing with aprepitant over multiple cycles was generally well tolerated. Compared with patients who received standard therapy alone (a 5-HT(3) antagonist plus dexamethasone), those who received aprepitant in addition to standard therapy had consistently better antiemetic protection that was well maintained over multiple cycles of highly emetogenic chemotherapy
Compared with patients who received standard therapy, those who received only the aprepitant regimen had better and more sustained protection against chemotherapy-induced nausea and vomiting over multiple cycles.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.