Dose-ranging antiemetic evaluation of the serotonin antagonist RG 12915 in patients receiving anticancer chemotherapy.
BACKGROUND
RG 12915 is a potent, selective 5-HT3 receptor antagonist with a biologic half-life of 11-20 hours. RG 12915 prevents cisplatin-induced emesis in ferrets at doses of 0.03 mg/kg. Animal toxicology studies permitted safe testing in humans at doses of up to 2.0 mg/kg. This dose-ranging trial of intravenous RG 12915 was performed to determine the optimal dosage and adverse effects and to observe for antiemetic effects in patients receiving anticancer chemotherapy.


METHODS
Twenty-six patients receiving chemotherapy likely to cause vomiting received a single intravenous dose of RG 12915 at a rate of 3 ml/minute beginning 60 minutes before chemotherapy. Four dose levels were explored: 0.25, 0.50, 1.0, and 2.0 mg/kg.


RESULTS
No dose-limiting toxicities were observed. All adverse effects were mild and transient and included discomfort at the infusion site, hyperglycemia, headache, serum aspartate transaminase (AST) and alanine transaminase (ALT) elevations, and sedation. Antiemetic efficacy was seen in patients receiving cisplatin at doses of greater than or equal to 100 mg/m2.


CONCLUSIONS
RG 12915 can be administered safely at the dose levels explored. Single intravenous doses of RG 12915 prevented or lessened emesis caused by chemotherapy, including cisplatin given at doses of greater than or equal to 100 mg/m2. RG 12915 warrants further testing. Of the doses tested, the 2.0 mg/kg dose is the most appropriate for further exploration.
Baltzer
L
L
Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York 10021.
Kris
M G
MG
Tyson
L B
LB
Rigas
J R
JR
Vreeland
F
F
Pisters
K M
KM
D000293:Adolescent; D000328:Adult; D000932:Antiemetics / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects; D001572:Benzofurans / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002945:Cisplatin / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy*; D012702:Serotonin Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
D000932:Antiemetics; D000970:Antineoplastic Agents; D001572:Benzofurans; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012702:Serotonin Antagonists; C065346:RG 12915; D002945:Cisplatin