Judith K. Evans

The Oral Neurokinin-1 Antagonist Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial in Patients Receiving High-Dose Cisplatin—The Aprepitant Protocol 052 Study Group

PURPOSE In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS Patients receiving cisplatin > or = 70 mg/m2 for the first time were 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 recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. RESULTS The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons). CONCLUSION Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy.

Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America.

Aprepitant is a novel neurokinin 1 (NK1) antagonist that has been shown to improve control of chemotherapy‐induced nausea and vomiting (CINV) when added to a standard antiemetic regimen of a 5‐hydroxytriptamine‐3 antagonist plus a corticosteroid. The authors sought to evaluate further the efficacy and tolerability of aprepitant plus standard therapy in a large clinical trial.

Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists

Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting

Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting

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.

The gastrointestinal safety of the COX-2 selective inhibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events

OBJECTIVE:Etoricoxib is a selective cyclooxygenase inhibitor that in clinical studies has improved the signs and symptoms of osteoarthritis and rheumatoid arthritis and reduced the potential for GI injury. The incidence of endoscopically detected ulcers and of clinically important upper GI events (perforations, ulcers, and bleeding episodes) was compared in patients taking etoricoxib or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs).METHODS:Upper GI endoscopy was performed at intervals over 12 wk in 680 patients taking etoricoxib 120 mg once daily, ibuprofen 800 mg three times daily, or placebo in a randomized, parallel-group, double-blind study. Survival analysis was used to analyze time-to-event data for the incidence of gastric or duodenal ulcers (≥3 mm and ≥5 mm), and the log rank test was used to compare the cumulative incidence between treatment groups. A combined analysis of upper GI events in all 10 Phase II/III clinical trials of etoricoxib (60, 90, or 120 mg) versus nonselective NSAIDs (naproxen, ibuprofen, or diclofenac) for osteoarthritis, rheumatoid arthritis, and chronic low back pain was conducted. Investigators reported potential events for adjudication by an external, blinded committee, using prespecified criteria to confirm events. All events that occurred during active treatment periods (maximum 792 days) or within 14 days of stopping treatment were included in the analysis. Time to first event was evaluated using survival analysis; the Kaplan–Meier method was used to determine the cumulative incidence, and relative risk was estimated with the Cox proportional hazards model.RESULTS:In the endoscopy study, the cumulative incidence of ulcers ≥3 mm at 12 wk in the ibuprofen group (17%) was significantly higher than in the etoricoxib group (8.1%, p < 0.001); similar results were seen for ulcers ≥5 mm. In the placebo group, the rate of ulcers ≥3 mm was 1.86%. Of 3142 patients treated with once-daily etoricoxib and 1828 patients treated with a nonselective NSAID (ibuprofen, naproxen, or diclofenac), 82 patients with investigator-reported upper GI events (71 confirmed) were eligible for the combined analysis. For etoricoxib versus NSAIDs, the rate per 100 patient-yr for confirmed events was 1.16 versus 3.05 (relative risk = 0.44, 95% CI = 0.27–0.72, p < 0.001), whereas that for investigator-reported events was 1.35 versus 3.42 (relative risk = 0.47, 95% CI = 0.30–0.74, p = 0.001). Results were driven primarily by studies with naproxen as the comparator.CONCLUSIONS:The incidence of endoscopically detected ulcers was significantly lower with etoricoxib 120 mg than with ibuprofen 2400 mg. Treatment with etoricoxib reduced the incidence of investigator-reported and confirmed adverse upper GI events by approximately 50% compared with treatment with nonselective NSAIDs.

A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting

BACKGROUND: Antiemetics currently in use are not totally effective. Neurokinin-1 receptor antagonists are a new class of antiemetic that have shown promise for chemotherapy-induced nausea and vomiting. This is the first study evaluating the efficacy and tolerability of the neurokinin-1 receptor antagonist, aprepitant, for the prevention of postoperative nausea and vomiting. METHODS: In this multicenter, double-blind trial, we randomly assigned 805 patients receiving general anesthesia for open abdominal surgery to a preoperative dose of aprepitant 40 mg orally, aprepitant 125 mg orally, or ondansetron 4 mg IV. Vomiting, nausea, and use of rescue therapy were assessed over 48 h after surgery. Treatments were compared using logistic regression. RESULTS: Incidence rates for the primary end point (complete response [no vomiting and no use of rescue] over 0–24 h after surgery, tested for superiority of aprepitant) were not different across groups (45% with aprepitant 40 mg, 43% with aprepitant 125 mg, and 42% with ondansetron). The incidence of no vomiting (0–24 h) was higher with aprepitant 40 mg (90%) and aprepitant 125 mg (95%) versus ondansetron (74%) (P < 0.001 for both comparisons), although between-treatment use of rescue and nausea control was not different. Both aprepitant doses also had higher incidences of no vomiting over 0–48 h (P < 0.001). No statistically significant differences were seen among the side effect profiles of the treatments. CONCLUSIONS: Aprepitant was superior to ondansetron for prevention of vomiting in the first 24 and 48 h, but no significant differences were observed between aprepitant and ondansetron for nausea control, use of rescue, or complete response.

Addition of the Oral NK1 Antagonist Aprepitant to Standard Antiemetics Provides Protection Against Nausea and Vomiting During Multiple Cycles of Cisplatin-Based Chemotherapy

PURPOSE This analysis evaluated whether the antiemetic efficacy of the NK1 receptor antagonist aprepitant (EMEND trade mark, Merck, Whitehouse Station, NJ) plus standard antiemetics could be sustained for up to six cycles of cisplatin-based chemotherapy. PATIENTS AND METHODS Patients receiving cisplatin > or = 70 mg/m2 were blindly assigned to receive one of the following three regimens: (1) aprepitant 375 mg 1 hour before cisplatin on day 1 and aprepitant 250 mg on days 2 to 5 (n = 35); (2) aprepitant 125 mg before cisplatin and aprepitant 80 mg on days 2 to 5 (n = 81); or (3) placebo before cisplatin on days 2 to 5 (n = 86). All groups received ondansetron 32 mg and dexamethasone 20 mg before cisplatin, and dexamethasone 8 mg on days 2 to 5. The primary end point was complete response (no emesis and no rescue therapy) over 5 days following cisplatin in up to six cycles. A cumulative probability analysis using a model for transitional probabilities was used to analyze the data. The aprepitant 375/250-mg regimen was discontinued early in light of new pharmacokinetic data. RESULTS In the first cycle, 64% of patients in the aprepitant group and 49% in the standard therapy group had a complete response. Thereafter, complete response rates for the aprepitant group were still 59% by cycle 6, but decreased to 34% by cycle 6 for the standard therapy group. Reasons for discontinuation were similar across treatment groups. CONCLUSION 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.

Rizatriptan 5 mg for the acute treatment of migraine in adolescents: A randomized, double-blind, placebo-controlled study

Objective.—To investigate the tolerability and efficacy of rizatriptan 5 mg in adolescent migraineurs.

Prevention of cisplatin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK-869 - A randomized controlled trial.

Recent studies have suggested that antiemetic therapy with a triple combination of the neurokinin‐1 receptor antagonist MK‐869, a serotonin (5‐HT3) antagonist, and dexamethasone provides enhanced control of cisplatin‐induced emesis compared with standard therapy regimens. The authors compared the antiemetic activity of a dual combination of MK‐869 and dexamethasone with that of a standard dual combination of ondansetron and dexamethasone to characterize further the efficacy and tolerability profile of MK‐869.

Evaluation of Potential Inductive Effects of Aprepitant on Cytochrome P450 3A4 and 2C9 Activity

The NK1 receptor antagonist aprepitant (EMEND®), developed for use in combination with a 5HT3 receptor antagonist and a corticosteroid to prevent highly emetogenic chemotherapy‐induced nausea and vomiting (CINV), has been shown to have a moderate inhibitory effect as well as a possible inductive effect on cytochrome P450 (CYP) 3A4. Aprepitant has been noted to produce modest decreases in plasma S(−)‐warfarin concentrations, suggesting potential induction of CYP2C9. Because metabolism of some chemotherapeutic agents may involve CYP3A4, the potential inductive effect of the CINV dosing regimen of aprepitant on this metabolic pathway was evaluated using intravenous midazolam, a sensitive probe substrate of CYP3A4. The time course of induction of CYP2C9 by aprepitant was also evaluated using oral tolbutamide, a probe substrate of CYP2C9. In this double‐blind, randomized, placebo‐controlled, single‐center study, 24 healthy subjects were randomized (12 subjects per group) to receive either an aprepitant 3‐day regimen (aprepitant 125 mg p.o. on day 1 and aprepitant 80 mg p.o. on days 2 and 3) or matching placebo. All subjects also received probe drugs (midazolam 2 mg i.v. and tolbutamide 500 mg p.o.) once prior to aprepitant dosing (baseline) and again on days 4, 8, and 15. The ratio (aprepitant/placebo) of the geometric mean area under the plasma concentration curve (AUC) fold‐change from baseline for midazolam was 1.25 on day 4 (p < 0.01), 0.81 on day 8 (p < 0.01), and 0.96 on day 15 (p = 0.646). The ratio (aprepitant/placebo) of the geometric mean AUC fold‐change from baseline for tolbutamide was 0.77 on day 4 (p < 0.01), 0.72 on day 8 (p < 0.001), and 0.85 on day 15 (p = 0.05). Assessed using intravenous midazolam as a probe, aprepitant 125/80 mg p.o. administered over days 1 to 3 produced clinically insignificant weak inhibition (day 4) and induction (day 8) of CYP3A4 activity and no effect on CYP3A4 activity on day 15. Assessed using oral tolbutamide as a probe, the aprepitant regimen also produced modest induction of CYP2C9 activity on days 4 and 8, which resolved nearly to baseline by day 15. Thus, the aprepitant regimen for CINV results in modest, transient induction of CYPs 3A4 and 2C9 in the 2 weeks following administration.