The clinical pharmacology of granisetron (BRL 43694), a novel specific 5-HT3 antagonist.

Granisetron is a novel specific 5-HT3 receptor antagonist whose effects have been evaluated in an extensive programme of volunteer studies. Single intravenous doses of 2.5-300 micrograms/kg of granisetron over 30 min, and of 40-160 micrograms/kg, administered over 3 min, were very well tolerated. There were no serious adverse events. There were no consistent or clinically important effects on cardiovascular parameters (pulse rate, blood pressure, ECG). Single doses of 40-200 micrograms/kg (30 min infusion) or 160 micrograms/kg (3 min infusion) did not influence subjective state, psychomotor performance or EEG. The only adverse event reported consistently more frequently with granisetron than placebo was constipation; this generally subsided spontaneously after 24-72 h. In volunteers, granisetron was widely distributed and also rapidly eliminated, largely through non-renal mechanisms. Granisetron exhibited essentially linear kinetics over the dose range studied (30-300 micrograms/kg). There was considerable inter-subject variability in terminal phase half-life and total plasma clearance. Biological activity of granisetron, as evidenced by significant inhibition of cutaneous 5-HT-induced, axon-reflex flare, was still apparent 24 h after a single dose of 40 micrograms/kg. Repeated intravenous doses of granisetron (up to 160 micrograms/kg b.d. for 7 days) were also well tolerated. As in the single dose studies, constipation was the only adverse event reported consistently more with active treatment than with placebo, but in no case did this necessitate withdrawal from the study or administration of a laxative.(ABSTRACT TRUNCATED AT 250 WORDS)