RG-12915

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.

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.

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.

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.

RG 12915 [4-[N-(1-azabicyclo[2.2.2.]octan-3-(S)-yl)]2-chloro-cis 5a-(S)-9a-(S)-5a,6,7,8,9,9a-hexahydrobenzofurancarboxamide hydrochloride] is a potent and effective agent against cisplatin-induced emesis in the ferret after i.v. or p.o. administration. This agent (p.o.) is also highly protective against cisplatin-induced emesis in the dog, as well as cyclophosphamide/doxorubicin-induced emesis in the ferret. When administered either p.o. or i.v., RG 12915 has a lower ED50 value (0.004 mg/kg) than GR 38032F, BRL 43694 and metoclopramide for attenuating cisplatin-induced emetic episodes in the ferret. It also has a long duration of action against cisplatin-induced emesis in the ferret. In contrast to metoclopramide, RG 12915 lacks significant antidopaminergic activity both in vitro [( 3H]spiroperidol displacement), as well as in vivo (apomorphine-induced emesis). In radioligand binding assays, RG 12915 is a potent and selective displacer of binding of 5-hydroxytryptamine (5-HT)3 binding sites (IC50 value = 0.16 nM), whereas failing to displace binding of ligands for the alpha-1, alpha-2 and beta adrenergic, 5-HT1 or 5-HT2 or cholinergic-muscarinic sites with IC50 values less than 1 microM. At a p.o. dose (1 mg/kg) in which RG 12915 is highly protective against cisplatin-induced emesis in the dog, RG 12915 has no significant gastroprokinetic activity in the same species. In summary, RG 12915 is a potent and p.o. effective agent against cytotoxic drug-induced emesis in animal models. The antiemetic potency of RG 12915 against cisplatin is unrelated to antidopaminergic or gastroprokinetic activity, but may be related to its affinity for 5-HT3 binding sites.