Tropisetron: A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential as an Antiemetic

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Abstract

Synopsis

Tropisetron is a potent and selective serotonin3 (5-hydroxytryptamine3; 5-HT3) receptor antagonist with antiemetic properties, probably mediated via antagonism of receptors both at peripheral sites and in the central nervous system. When compared with antiemetic regimens containing high-dose metoclopramide in a small number of studies, tropisetron was generally as effective at preventing acute and delayed vomiting induced by high-dose cisplatin (≥50 mg/m2). In these studies tropisetron completely prevented vomiting occurring in the first 24 hours after chemotherapy in 35 to 76% of patients. Tropisetron was superior to alizapride in preventing emesis induced by high-dose alkylating agents. The effectiveness of tropisetron in patients who had previously had partial control of emesis was improved by the addition of dexamethasone.

Synopsis

Tropisetron appears to be well tolerated with the most frequently reported adverse effect being headache. Extrapyramidal effects, which can occur in 5 to 10% of patients receiving high-dose metoclopramide and which may limit its use, have been reported in only isolated cases with tropisetron.

Synopsis

Thus, tropisetron is an effective, apparently well tolerated agent which can be administered once daily for the prevention of chemotherapy-induced nausea and vomiting. However, further clinical experience is needed to clarify the optimum role of tropisetron as an antiemetic agent, particularly with regard to other drugs in its class. Nonetheless, preliminary results indicate that tropisetron will be a useful alternative for use in controlling emesis induced by cytotoxic therapy.

Pharmacodynamic Properties

Tropisetron is a potent and selective antagonist at serotonin3 (5-hydroxytryptamine; 5-HT3) receptors. It is also a weak antagonist at 5-HT4 receptors but has no significant affinity for 5-HT1, 5-HT2, dopamine D2 or benzodiazepine receptors, or adrenoceptors. Studies in various animal models of emesis have shown that intravenously administered tropisetron reduced the incidence of, or completely abolished, vomiting and retching induced by cytotoxic drugs such as cisplatin. Cytotoxic drugs cause gastrointestinal cellular damage which may result in the release of serotonin, activating vagal and possibly splanchnic afferent neurons which elicit the vomiting response. Tropisetron probably prevents emesis induced by cytotoxic agents by antagonising the effects of serotonin both at a peripheral (vagal) site and in the central nervous system at the terminus for vagal afferent fibres. In the ferret, subcutaneously administered tropisetron also inhibited radiation-induced emesis.

Pharmacokinetic Properties

After single dose oral administration of tropisetron 20 or 100mg to healthy volunteers, mean peak plasma concentrations of 24.7 and 173 μg/L occurred 1.3 and 1.1 hours post-dose, respectively. Tropisetron undergoes dose-dependent first-pass hepatic metabolism, the absolute bioavailability of a 20 and 100mg dose being 52 and 66%, respectively. Tropisetron has high tissue affinity with a volume of distribution of 554L following intravenous administration.

Pharmacokinetic Properties

Tropisetron is metabolised by the liver cytochrome P450 2D6 enzyme system and due to polymorphism of this system some patients metabolise tropisetron faster than others. The mean elimination half-lives following intravenous and oral administration were 7.3 and 8.6 hours, respectively, in volunteers classified as extensive metabolisers, and 30.3 and 41.9 hours, respectively, in volunteers classified as poor metabolisers. Approximately 80% of a dose is excreted via the kidneys, mainly as metabolites. Metabolic clearance is decreased in patients with impaired hepatic or renal function. However, in view of the short term nature of the recommended treatment regimen, dose adjustment in poor metabolisers, or inpatients with hepatic or renal dysfunction, is not required.

Therapeutic Efficacy

Dose-finding studies in cancer patients receiving chemotherapy have shown no significant difference in the antiemetic response to single intravenous doses of tropisetron 5, 10, 20 or 40mg. Most clinical trials involved intravenous administration of tropisetron to patients prior to chemotherapy followed by oral administration for up to 5 days afterwards. In various noncomparative trials, tropisetron was generally more effective in completely controlling nausea and vomiting occurring in the first 24 hours after chemotherapy (47 to 73% of patients) than nausea and vomiting occurring 2 to 6 days after chemotherapy (12 to 60% of patients). In one study, the efficacy of tropisetron was sustained over 3 courses of chemotherapy but thereafter appeared to decrease. Tropisetron was effective in preventing chemotherapy-induced emesis in children.

Therapeutic Efficacy

In the few comparative trials conducted to date, tropisetron was generally as effective as standard antiemetic regimens, some of which included high-dose metoclopramide, in controlling both acute and delayed vomiting in cisplatin-treated patients. In these studies, vomiting was completely controlled in the first 24 hours after chemotherapy in 35 to 76% of patients treated with tropisetron and in 25 to 63% of patients treated with standard antiemetic regimens; however, most of these studies were not conducted using a double-blind protocol and details of the standard regimens were not always reported. Tropisetron was superior to alizapride in preventing emesis occurring during the 72 hours after high-dose cyclophosphamide or melphalan administration.

Therapeutic Efficacy

Tropisetron in combination with dexamethasone was more effective than tropisetron monotherapy in patients who had a partial response to tropisetron alone in their first course of cisplatin-based chemotherapy. In a retrospective comparison, the efficacy of tropisetron in preventing emesis occurring during the 72 hours after high-dose alkylating agent chemotherapy appeared to be improved by the addition of haloperidol. Ondansetron was more effective than tropisetron, both in combination with dexamethasone, in preventing acute vomiting in patients following non-cisplatin chemotherapy. However, further studies are needed to confirm the results of this nonblind, crossover study.

Therapeutic Efficacy

Tropisetron was more effective than placebo in preventing postoperative nausea and vomiting in patients following gynaecological surgery. In a noncomparative trial in patients receiving tropisetron for radiotherapy-induced emesis the percentage of days per week during which nausea occurred increased over the 6-week study period from 13 to 32%.

Tolerability

In clinical trials tropisetron appeared to be well tolerated with the most frequently reported adverse effect being mild headache. Other adverse effects included constipation, diarrhoea and fatigue. Transient changes in blood pressure have been reported which resolved without treatment. Extrapyramidal effects, which occur in 5 to 10% of patients treated with metoclopramide, have been reported in only 3 patients (0.7%) treated with tropisetron. The relationship of these symptoms (muscle cramps or ataxia) to tropisetron treatment was not determined.

Dosage and Administration

Dose-finding studies have shown that 5 to 40mg doses of tropisetron administered prior to chemotherapy are equally effective in preventing nausea and vomiting. A simple 6-day course of tropisetron 5mg daily, administered by intravenous infusion or slow intravenous injection before chemotherapy and orally for the following 5 days is recommended. For this 6-day course no dosage reduction is required in patients with impaired hepatic or renal function, or patients classified as poor metabolisers.

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