Single Oral Dose of Antiemetic Agent Is Effective

Nick Mulcahy

May 14, 2009

May 14, 2009 — In preventing chemotherapy-induced nausea and vomiting (CINV), a single oral dose of a new neurokinin-1-receptor antagonist, casopitant, works as well as a multiple-day oral and intravenous dosing of the same agent, according to the results of a phase 3 study.

Casopitant is not yet approved in any form. Currently, there is only 1 other neurokinin-1-receptor antagonist, aprepitant (Emend, Merck). Aprepitant can also be used in a single dose, but only intravenously; the oral form is dosed for 3 days. Aprepitant is approved by the US Food and Drug Administration and by the European Medicines Agency.

If approved in a single-dose formulation, casopitant would be the only single-dose oral neurokinin-1-receptor antagonist for CINV.

"Since the single dose was at least as effective as multiple doses and is much more convenient for patients, this might become the preferred schedule for administration," lead author of the study, Steven Grunberg, MD, told Medscape Oncology. Dr. Grunberg is from the University of Vermont in Burlington. The study was published online May 8 in the Lancet Oncology.

We suspected that aggressive protection on the first day would be enough to prevent emesis for the full 5-day period.

"We suspected that aggressive protection on the first day would be enough to prevent emesis for the full 5-day period," added Dr. Grunberg.

Several consensus guidelines now recommend that a neurokinin-1-receptor antagonist be used with other antiemetics to prevent CINV in patients receiving highly emetogenic chemotherapy, note the authors.

In this phase 3 study, casopitant was given as part of a 3-drug antiemetic regimen, along with ondansetron (Zofran, GlaxoSmithKline) and the glucocorticosteroid dexamethasone, to patients with solid tumors receiving highly emetogenic cisplatin-based regimens.

An important part of the value of neurokinin-1-receptor antagonists is in preventing CINV during its delayed phase (24–120 hours after the initiation of therapy), write Dr. Grunberg and his colleagues.

Serotonin type 3 (5-HT3) receptor antagonists such as ondansetron have improved the management of CINV, especially emesis, during the acute phase (0–24 hours after initiation of therapy). However, these agents often fail or offer only moderate improvement during the delayed phase, explain the study authors.

Half of our patients still have nausea or vomiting in the 2 to 5 days after they go home.

"In spite of previous antiemetic agents and the excellent protection we achieve initially on the day of chemotherapy, half of our patients still have nausea or vomiting in the 2 to 5 days after they go home," said Dr. Grunberg about the problem of delayed emesis.

Casopitant Significantly Reduced CINV vs Placebo

In this multicenter, multinational study, 810 patients with malignant solid tumors, such as those with non-small-cell lung cancer and head and neck cancer, were scheduled to receive cisplatin-based regimens, which cause CINV in almost all patients.

All participants received the antiemetics dexamethasone and ondansetron, and were randomized to additionally receive placebo (control), a single oral dose of casopitant mesylate (150 mg), or 3-day intravenous plus oral casopitant mesylate (90 mg intravenous on day 1 plus 50 mg oral on days 2 and 3).

The primary end point of the study, complete response, was defined as no vomiting and no use of rescue medications for nausea.

Significantly more patients in each casopitant group achieved complete response in cycle 1 of chemotherapy than did those in the control group.

Specifically, 66% of patients in the control group had a complete response, compared with 86% in the single-dose oral casopitant mesylate group (P < .0001 vs control) and 80% in the 3-day intravenous plus oral casopitant mesylate group (P = .0004 vs control).

These proportions of improvement were sustained over multiple cycles of the chemotherapy, write the investigators.

Patients in the study were used to assess efficacy and were asked to use a daily diary to record their use of any rescue medication, the number and time of any emetic events, and the maximum nausea experienced in the previous 24 hours (as measured by a visual analogue scale).

The patients also assessed their quality of life by completing a self-administered questionnaire, the Functional Living Index–Emesis (FLIE), at baseline and on day 6 of the first cycle of chemotherapy.

Based on the FLIE tabulations, 64% of patients in the control group reported that CINV had no effect on daily activities, compared with 77% and 78% of patients in the single-dose oral and 3-day intravenous and oral casopitant groups, respectively.

increasing the overall satisfaction is an indication that we are on the right track.

However, only 58% of patients in each of the casopitant mesylate groups indicated that they were very satisfied with the antiemetic therapy, compared with 51% of patients in the control group.

When asked about the somewhat comparable levels of very satisfied patients among the treatment groups, Dr. Grunberg accented the positive and said that "increasing the overall satisfaction is an indication that we are on the right track."

More Serious Events with Casopitant

Adverse events occurred in 77% of patients in the single-dose oral casopitant group, 75% of patients in the 3-day intravenous and oral casopitant group, and 73% of patients in the control group.

Both casopitant-treatment groups had a greater proportion of serious adverse events (16%) than the control group (11%).

The most commonly reported adverse events were those associated with cisplatin-based chemotherapy, write the authors, who also said the incidence was within the expected range.

However, the investigators did an ad hoc analysis in an effort to identify the cause of higher rates of neutropenia in the casopitant groups. The 3-day intravenous and oral casopitant group had a 40% rate of neutropenia, compared with 30% for controls.

The analysis revealed that a higher proportion of patients on cisplatin plus either vinorelbine or etoposide chemotherapy regimens had grade 4 neutropenia.

"Casopitant mesylate is a moderate inhibitor of CYP3A, and vinorelbine and etoposide are metabolized by CYP3A; thus, coadministration of these agents might have resulted in higher levels of the chemotherapeutic agents, which, in turn, might have produced a greater incidence of grade 4 neutropenia," they speculate.

The study was sponsored by GlaxoSmithKline. Dr. Grunberg is a consultant to the company. A number of the study authors are company employees and own stock in the company.

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