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 in brainstem regions associated with emesis. Based on studies in the ferret, it was postulated that a neurokinin-1 (NK1) receptor antagonist would have antiemetic activity as monotherapy in humans receiving chemotherapy. L-758,298 is a water-soluble, intravenous (i.v.) prodrug for L-754,030, a potent and selective NK1 receptor antagonist. This double-blind, randomised, active-agent (ondansetron)-controlled study enrolled 53 cisplatin-naïve 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 ondansetron (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 revealed no significant difference between the groups. In the delayed period, the proportion of patients without emesis in the L-758,298 and ondansetron treatment 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 group 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 proposition that the underlying mechanism(s) of acute and delayed emesis are different.
Cocquyt
V
V
Vlaamse Oncologische Studiegroep, Ghent, Belgium.
Van Belle
S
S
Reinhardt
R R
RR
Decramer
M L
ML
O'Brien
M
M
Schellens
J H
JH
Borms
M
M
Verbeke
L
L
Van Aelst
F
F
De Smet
M
M
Carides
A D
AD
Eldridge
K
K
Gertz
B J
BJ
D000080:Acetals / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000932:Antiemetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000077608:Aprepitant; D002945:Cisplatin / Q000009:adverse effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000627:therapeutic use*; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control*; D017294:Ondansetron / Q000627:therapeutic use*; D017060:Patient Satisfaction; D011355:Prodrugs; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
D000080:Acetals; D000932:Antiemetics; D000970:Antineoplastic Agents; C400262:L 758298; D009025:Morpholines; D011355:Prodrugs; D000077608:Aprepitant; D017294:Ondansetron; D002945:Cisplatin