Comparison of L-758,298, a prodrug for the selective neurokinin-1 antagonist, L-754,030, with ondansetron for the prevention of cisplatin-induced emesis

Substance P is localised ill brainstem regions associated with emesis. Base d on studies in the ferret, it was postulated that a neurokinin-1 (NK1) rec eptor antagonist would have antiemetic activity as monotherapy in humans re ceiving chemotherapy. L-758,298 is a water-soluble, intravenous (i.v.) prod rug for L-754,030, a potent and selective NK1 receptor antagonist. This dou ble-blind, randomised, active-agent (ondansetron)-controlled study enrolled 53 cisplatin-naive patients and evaluated the prevention of both acute (0- 24 h) and delayed (days 2-7) emesis after cisplatin treatment (50-100 mg/m( 2)). All patients received i.v. L-758,298 (60 or 100 mg) (n=30) or ondanset ron (32 mg) (n=23) before cisplatin and efficacy was evaluated up to day 7 post-cisplatin. Nausea was assessed by means of a four-point ordinal scale at intervals over the 7 day period. In the acute period, the proportion of patients without emesis in the L-758,298 and ondansetron groups was 37 and 52%, respectively (no significant difference between the groups), Comparing the distribution of average nausea scores over the entire first 24 h revea led no significant difference between the groups. In the delayed period. th e proportion of patients without emesis in the L-758,298 and ondansetron tr eatment groups was 72 and 30%, respectively (P=0.005), The distribution of average nausea scores in the delayed period was lower in the L-758,298 grou p compared with the ondansetron group (P=0.15 for the entire delayed period and P=0.043 for day 2 only). No serious adverse events were attributed to L-758,298. A single dose of L-758,298 substantially suppressed the delayed nausea and vomiting characteristic of high dose cisplatin and also appeared to reduce acute emesis post-cisplatin. The data also support the propositi on that the underlying mechanism(s) of acute and delayed emesis are differe nt. (C) 2001 Elsevier Science Ltd. All rights reserved.