Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 24, No 18S (June 20 Supplement), 2006: 18601
© 2006 American Society of Clinical Oncology

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Abstract

Complete rescue from established emesis by the NK-1 receptor antagonist, casopitant mesylate, in cisplatin-induced delayed emesis in the ferret

GlaxoSmithKline, Collegeville, PA

18601

Background: Postoperative and chemotherapy-induced nausea and vomiting (PONV, CINV) can be major complications in patients undergoing surgery or cancer treatment with emetogenic drugs. Nausea and vomiting may extend beyond the postoperative recovery period or in a delayed manner following chemotherapy. Prophylaxis with 5-HT₃ receptor antagonists may fail in some patients, requiring the use of rescue medications. Selective NK-1 receptor antagonists provide incremental improvement in efficacy when used in combination with 5-HT₃ antagonists and dexamethasone, both in preclinical animal models and in the clinical setting. Methods: The anti-emetic and anti-nausea properties of a potent and selective NK-1 receptor antagonist, casopitant mesylate (GW679769), were evaluated in the ferret using single-dose rescue treatment in a cisplatin-based delayed emesis model. In the delayed model (72 hr), a single dose of saline, ondansetron, or casopitant mesylate was administered ip at 44.8 hrs post cisplatin (5 mg/kg, ip). This time corresponds to peak emetic frequency in this model. Results: Ondansetron (1 mg/kg) significantly delayed further emetic events for 8 hours post injection. Emetic frequency after this latency period then paralleled the saline treated group. In contrast, casopitant mesylate resulted in an immediate dose-dependent rescue from further emetic events, with minor effects on latency. Complete rescue from further emetic events were achieved at casopitant mesylate doses 0.5 mg/kg. Casopitant mesylate rescue treatment also reduced nausea-like behaviors in a dose-dependent manner; however, higher doses were required to achieve statistical significance. Conclusions: Single-dose ondansetron rescue treatment failed to reduce nausea-like behaviors. These unique results, along with previously described anti-emetic prophylactic activity, support the ongoing clinical evaluation of casopitant mesylate, which is currently in phase III trials for the prevention of PONV and CINV from moderately and highly emetogenic chemotherapy. It is also in clinical development for depression and anxiety.

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