Granisetron

Summary

Synopsis

Granisetron (BRL 43694) is a highly selective 5-HT₃ receptor antagonist which possesses significant antiemetic activity, likely mediated through antagonism of 5-HT₃ receptors on abdominal vagal afferents and possibly in or near the chemoreceptor trigger zone. Clinical trials in cancer patients demonstrate that, compared with placebo, granisetron significantly reduces the incidence of nausea and vomiting for 24 hours after administration of high-dose cisplatin. In large comparative trials, 70% of patients who received granisetron prior to cisplatin or other chemotherapy experienced complete inhibition of vomiting with little or no nausea for 24 hours after antineoplastic administration; these results were similar to those obtained with high-dose metoclopramide plus dexamethasone, and superior to a combination of chlorpromazine plus dexamethasone, or prochlorperazine plus dexamethasone, or methylprednisolone monotherapy. The most frequently reported adverse event associated with granisetron administration is headache which occurs in about 10 to 15% of patients while constipation, somnolence, diarrhoea and minor transient changes in blood pressure have been reported less frequently. Extrapyramidal effects, which can occur with high-dose metoclopramide and may be a limiting factor in its use, have not been noted with granisetron administration.

Thus, granisetron is an effective, well tolerated and easily administered agent for the prophylaxis of nausea and vomiting induced by cancer chemotherapy which appears to be devoid of extrapyramidal side effects associated with metoclopramide. As a member of a new class of drugs, the selective 5-HT₃ receptor antagonists, granisetron provides the medical oncologist with a new, potentially more acceptable antiemetic therapy.

Pharmacodynamic Properties

Granisetron is a potent and selective antagonist of 5-HT₃ receptors in the peripheral as well as central nervous system. It inhibits various effects on isolated animal tissues induced by serotonin including contractions of guinea-pig ileum and tachycardia of rabbit heart. In addition, granisetron blocks the depolarising effects of serotonin in the rabbit vagus nerve which are mediated by 5-HT₃ receptors. Binding studies show no significant interaction with other receptors. 5-HT₃ receptors have also been identified in the area postrema (the chemoreceptor trigger zone for emesis), the nucleus tractus solitarius and in greater concentrations in the brain stem, the main terminus for vagal afferent fibres. Granisetron has 4000 to 40 000 times greater affinity for5-HT₃ receptors in rat and guinea-pig brain than for other receptors studied including 5-HT₁, 5-HT₂, dopamine D₂, histamine H₁, benzodiazepine and opioid receptors.

Antiemetic studies in the ferret showed that parenteral or oral administration of granisetron reduced the incidence of, or completely prevented, emesis induced by radiation or cytotoxic drugs, including cisplatin. In humans and animals already experiencing cytotoxic-induced vomiting, granisetron completely and rapidly abolished emesis. In the ferret, emesis stopped within 15 to 60 seconds of parenteral granisetron administration. These cytotoxic stimuli cause cellular damage, which may precipitate the release of serotonin from enterochromaffin cells of the intestinal mucosa, activating vagal and possibly splanchnic afferent neurons, which elicit the vomiting response. Granisetron probably prevents nausea and vomiting evoked by antineoplastic drugs and radiation by antagonising the effects of serotonin at 5-HT₃ receptors on the abdominal afferents supplying the upper small intestine and possibly in the nucleus tractus solitarius or the area postrema.

Pharmacokinetic Properties

After rapid intravenous administration of granisetron 20 or 40 μg/kg to healthy volunteers, mean peak plasma concentrations were 13.7 and 42.8 μg/L, respectively. Peak plasma concentrations and area under the plasma concentration-time curve (AUC) increase roughly in proportion to dose, while half-life, volume of distribution and clearance values remain essentially unchanged, indicating linear kinetics over a wide range of dosages (10 to 300 μg/kg). The volume of distribution of granisetron is 2.2 to 3.3 L/kg in cancer patients. Mean plasma half-life is longer in cancer patients (about 10 to 12 hours) than in healthy volunteers (3.1 to 5.9 hours). Furthermore, total body clearance values are lower and AUC values are higher in cancer patients, and together, these findings may reflect differences in drug elimination due to underlying disease processes, increased age of cancer patients relative to healthy volunteers or other factors. Elimination of granisetron is primarily by non-renal mechanisms, with only 8 to 15% of the parent compound recovered in the urine.

Therapeutic Use

Most clinical trials involved the intravenous administration of granisetron to cancer patients, 5 minutes prior to a variety of chemotherapeutic regimens, and have evaluated its antiemetic efficacy over the following 24-hour period, continuing with evaluation during the next 6 days. Dose-finding studies showed no significant difference in the antiemetic response of cancer patients receiving chemotherapy to single intravenous doses of granisetron 40 μg/kg and 160 μg/kg (with 1 or 2 supplemental doses of 40 μg/kg allowed for breakthrough symptoms). Emesis was completely inhibited, with no or only mild nausea in 57 to 81% of patients in these studies. Granisetron was significantly superior to placebo in preventing emesis evoked by cisplatin, and was very effective as an intervention agent, quickly abolishing emesis in most patients unresponsive to placebo. Granisetron was at least as effective over the initial 24 hours following chemotherapy as a combination of high-dose metoclopramide plus dexamethasone with or without diphenhydramine, and was superior to chlorpromazine plus dexamethasone, or prochlorperazine plus dexamethasone, or methylprednisolone monotherapy. In the larger comparative studies, granisetron completely prevented emesis in 70% of cancer patients for the 24 hours after receiving chemotherapy. The antiemetic efficacy of granisetron over 7 days following chemotherapy is equivalent to combinations of high-dose metoclopramide plus dexamethasone, or chlorpromazine plus dexamethasone, or alizapride plus dexamethasone. In a noncomparative trial, 56% of patients receiving granisetron did not experience emesis or nausea during the initial 24 hours following total body irradiation, and only 19% of patients reported emesis over the next 6 days.

Tolerability

Granisetron was generally well tolerated in clinical trials. The most frequent adverse event observed with granisetron administration was headache, which occurred in about 10 to 15% of patients. Other less frequently reported adverse events included constipation, somnolence and diarrhoea. Transient changes in blood pressure were also observed which resolved without treatment in all cases and were generally considered to be clinically insignificant. Extrapyramidal effects, which occur in up to 5% of patients receiving high-dose metoclopramide, were not experienced with granisetron administration in any study.

Dosage and Administration

Little or no difference in antiemetic efficacy and tolerability was observed in clinical trials comparing low doses (40 μg/kg) with high doses (160 μg/kg). In most studies, single intravenous doses of 40 to 160 μg/kg were administered 5 minutes before chemotherapy, and up to 2 supplemental doses of 40 μg/kg were permitted during the initial 24 hours for breakthrough symptoms. Granisetron was usually diluted in normal saline and administered intravenously over 2 to 30 minutes. The manufacturer has simplified the dosage regimen to a standard fixed 3mg intravenous dose infused over 5 minutes.