DR G EVALUATIO

Drugs 42 (5): 805-824. 1991 00 12-6667/91 /0011-0805 /$10.00 /0 © Adis International Limited . All rights reserved. DREl68

Granisetron

A Review of its Pharmacological Properties and Therapeutic Use as an Antiemetic Greg L. Plosker and Karen L. Goa Adis International Limited , Auckland, New Zealand

Various sections of the manuscript reviewed by: MS. Aapro, Clinique de Genolier, Centre pluridisciplinaire de Cancerologie, Genolier, Switzerland; P.R. Andrews, Department of Physiology,St George's Hospital Medical School, Un iversity of London , London , England; N.M. Barnes, Department of Pharmacology, University of Birmingham Medical School, Birmingham , England; C Erlichman, Ontario Cancer Institute, Princess Margaret Hospital, Toronto , Ontario, Canada; C/. Fa/bon, Department of Medical Oncology, University of Pretoria, Pretoria, South Africa; H.C Fa/kson, Department of Medical Oncology, University of Pretoria, Pretoria, South Africa; R.A. Joss, Department of Oncology, Medizinische Klinik, Kantonsspital Luzern, Lucerne, Switzerland; T. Machida, Department of Urology, Jikei University School of Medicine, Tokyo, Japan; M. Marty, Service d'Oncologie Medicale, Centre des Maladies du Sein, Hopital Saint Louis, Paris, France; S.J. Peroutka, Departments of Neurology and Pharmacology, Stanford University Medical Center, Stanford , California, USA.; M. Soukop, Medical Oncology, Royal Infirmary, Glasgow, Scotland; P.L. Trio zzi, Division of Hematology and Oncology, Ohio State Un iversity, Columbus, Ohio , USA.

Contents 806 808 808 8/0 8/0

8/2 8/2 8/2

8/3 8/4 8/4 8/5 8/6 8/6 8/9

820 820 82/

Summary I. Pharmacodynamic Properties I.I Activity at 5-HT3 Receptors, and Selectivity of Action 1.2 Antiemetic Effects 1.3 Mechanism of Action 2. Pharmacokinetic Properties 2.1 Plasma Concentrations and Distribution 2.2 Elimination 2.3 Relationship Between Plasma Concentration and Clinical Efficacy 3. Therapeutic Use 3.1 Cytotoxic Drug-Induced Nausea and Vomiting 3.1.1 Dose-Finding Studies 3.1.2 Comparisons With Placebo 3.1.3 Comparisons With Other Antiemetic Agents 3.2 Radiation-Induced Nausea and Vomiting 4. Tolerability 5. Dosage and Administration 6. Place of Granisetron in Antiemetic Therapy

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Summary Synopsis Granisetron (BRL 436 94) is a highly selective 5-HTJ receptor antagonist which possesses significant antiemetic activity. likely media ted through antagonism of5-H TJ receptors on abdominal vagal afferents and possibly in or near the chemo receptor trigger zone. Clinical trials in cancer patients demonstrate that. compared with placebo. granisetron significantly reduces the incidence of nausea and vomiting fo r 24 hours after adm inistration 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 fo r 24 hours after antin eoplastic adm inistration; these results were sim ilar to those obtained with high-dose metoclopramide plus dexamethasone. and superior to a combination of chlorpromazine plus dexamethasone. or prochlorperazine plus dexamethasone, or methylprednisolone monoth erapy. The m ost frequently reported adverse event associated with granisetron administration is headache which occurs in about IOto 15% ofpatients 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 f or 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 ofa new class of drugs. the selective 5-HTJ receptor antagonists, granisetron provides the medical oncologist with a new, potentially more acceptable antiemet ic 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 tach ycardia of rabbit heart. In add ition , granisetron blocks the depolarising effects of serotonin in the rabb it 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 affinit y for 5-HT3 receptors in rat and guinea-pig brain than for other receptors studied including 5-HT I, 5-HT2, dopam ine D2, histamine HI , 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 ant ineoplastic drugs and radiation by antagonising the effects of serotonin at 5-HT 3 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 intrave nous administration of granisetron 20 or 40 ltg/kg to health y volunteers, mean peak plasma concentrations were 13.7 and 42.8 Itg/L, respectivel y. Peak plasma concentrations and area under the plasma concentration-time curve (AVC) increase roughl y in proportion to dose, while half-life, volume of distribution and clearance values rema in essentially unchanged, indicating linear kinetics over a wide range of dosages (10 to 300 ltg/kg). The volume of distribution of granisetron is 2.2 to 3.3 L/kg in cancer patients. Mean plasma half-life is longer

Granisetron: A Review

807

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 AVe 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 ltg/kg and 160 ltg/kg (with I or 2 supplemental doses of 40 ltg/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. Granisctron 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 admin istration 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 ltg/kg) with high doses (160 ltg/kg). In most studies, single intravenous doses of 40 to 160 ltg/kg were administered 5 minutes before chemotherapy, and up to 2 supplemental doses of 40 ltg/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.

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Drugs 42 (5) 1991

Granisetron (BRL 43694) is an azabicyclic compound (fig. I) which is a potent and selective antagonist of serotoninj (5-hydroxytryptam ine3, 5HT3) receptors (Fake et al. 1987). Nausea and vomiting induced by cytotoxic agents are thought to be mediated at least in part by 5-HT3 receptors (Blower 1990; Joss et al. 1990; King & Sanger 1989). The vomiting centre in the medullary reticular formation of the brainstem coordinates the act of vomiting through input from the periphery, including vagal afferents, higher central nervous system structures and the chemoreceptor trigger zone for emesis, located in the area postrema (Andrews et al. 1988; Joss et al. 1990). In light of the distribution of 5-HT3 receptors in these regions, and the established pharmacodynamic action of 5-HT3 receptor antagon ists, granisetron and other agents in this class have potential therapeutic application in the prevention and treatment of cytotoxic-induced

Granisetron

Ondansetron

nausea and vomiting (King & Sanger 1989), adverse events which are very distressing and may result in dose limitation or patient refusal to continue antitumour therapy. In add ition to 5-HT3 receptors, several other receptors or binding sites, including dopaminergic , cholinergic, histaminergic and opioid , have been identified in the area postrema and dorsal vagal complex, and may be involved in cytotoxic druginduced emesis (Leslie 1985). Since the development of nausea and vomiting involves peripheral as well as central input , agents with anxiolytic, amnestic or gastric prokinetic activity may also play an important role in controlling these symptoms (Joss et al. 1990). Consequently, a variety of agents, alone or in combination, have been used in the treatment of cytotoxic drug-induced nausea and vomiting. One of the standard antiem etic agents utilised is metoclopramide, which blocks dopamine 0 2 receptors at low doses (e.g. 10 to 30mg) and antagonises 5-HT3 receptors at high doses (e.g. 2 mg/kg)[Blower 1990; Miner & Sanger 1986; Tabona 1990]. This knowledge has helped to develop a new class of antiemetic agents which are specific 5-HT3 receptor antagonists and includes granisetron , ondansetron and tropisetron. Because of their selective action at 5-HT3 receptor sites, these drugs may also have potential applications in the treatment of other 5-HT3-mediated disorders such as visceral and chemically-induced pain, schizophrenia, migraine headache, cognitive disorders and anxiety (Barnes et al. 1991 ; Couturier et al. 1991 ; Jones 1990; King & Sanger 1989; Montgomery & Fineberg 1989;Moss & Sanger 1990). However, this review focuses on the use of granisetron as an antiemetic agent in cytotoxic-induced nausea and vomiting.

1. Pharmacodynamic Properties 1.1 Activity at 5-HT3 Receptors, and Selectivity of Action

Serotonin (5-HT) Fig. 1. Chemical structures of grani setron , ondansetron and sero to nin (5-HT) .

Serotonin receptors have been classified into several subtypes following development and application of radioligand binding techniques. These receptor subtypes include 5-HTI A, 5-HTIB, 5-

Granisetron: A Review

HTIC, 5-HTID, 5-HTIE, 5-HT2, 5-HTJ (formerly serotonin M) and possibly 5-HT 4 (Bradley et al. 1986; Leonhardt et al. 1989; Montgomery & Fineberg 1989; Peroutka 1988; Yoshida et al. 1991). Clinically, serotonin has been implicated in a number of disorders; however, only limited data are available to establish the clinical functions associated with each serotonin receptor subtype (Montgomery & Fineberg 1989; Peroutka 1988). Although 5-HTJ receptors exhibit heterogeneity, implying the existence of possible 5-HTJ subtypes , these have yet to be defined and may only suggest the presence of species differences (Bradley et al. 1986; Montgomery & Fineberg 1989; Peroutka 1988). As evidenced by animal and human studies in vitro, 5-HTJ receptors are located both peripherally and centrally . 5-HT3 receptors have been ident ified in peripheral isolated tissue models such as the rat vagus nerve (Ireland & Tyers 1987), guinea-pig ileum (Buchheit et al. 1985) and rabbit heart (Fozard et al. 1979). However, both animal and human studies have demonstrated that 5-HT3 receptors are distributed with highest density in the dorsomedial region of the nucleus tractus solitarius, the primary terminus for abdominal vagal afferent fibres, and in and near the area postrema of the medulla oblongata, the site of the chemoreceptor trigger zone for emesis (Barnes et al. 1988, 1989b, 1990a; Higgins et al. 1989; Kilpatrick et al. 1989; Leslie et al. 1990; Pratt & Bowery 1989; Pratt et al. 1990; Reynolds et al. 1989). Studies using radiolabelled 5H'I'j-selective ligands such as GR65630 have also identified 5-HT3 binding sites in cortical and limbic areas of various animal species (Ashby et al. 1989; Barnes et al. 1989a; Kilpatrick et al. 1987, 1989). In post-mortem human brain, a relatively high level of specific [JH]GR65630 binding was detected in the amygdala and hippocampus, while a low level of specific binding was detected in cortical areas and the cerebellum (Kilpatrick et al. 1989). Granisetron is a potent and selective competitive antagonist of 5-HT3 within the peripheral and central nervous systems. Its peripheral effects are demonstrated by its ability to inhibit serotonin-

809

evoked contractions of guinea-pig isolated ileum, and tachycardia of isolated rabbit heart (at low nmol/L concentrations), which are mediated by 5HT 3 receptors (Fake et al. 1987; Sanger & Nelson 1989). Furthermore, granisetron and other agents exhibiting a high affinity for 5-HT3 binding sites in the rat brain, strongly inhibit the serotonin-induced Bezold-Jarisch reflex (bradycardia) in the rat, which is a functional assessment of peripheral 5HT 3 receptor antagonism (Nelson & Thomas 1989). Granisetron also inhibits serotonin-induced depolarisation and reduction of C spike in the rabbit vagus nerve, events which are elicited by stimulation of 5-HT3 receptors (Elliott et al. 1990). Except at a high concentration (l00 jlmol/L), granisetron has no effect on electrically induced, choline rgically mediated contractions of guinea-pig ileum , rat forestomach or human stomach (Sanger & Nelson 1989). When granisetron was administered in a concentration (10 nmol/L) that almost totally prevented the depolarising response to serotonin in the rabbit vagus nerve, responses to 'Yaminobutyric acid (GABA) and DMPP (a nicotinic receptor ligand) were unchanged (Elliott et al. 1990). Radioligand studies in the central nervous system demonstrated that granisetron has little or no affinity for 5-HTIA, 5-HTJB, 5-HT2, dopamine DI and D2, histamine HI , benzodiazepine, picrotoxin, ai , a2 or iJ-adrenergic receptor binding sites in rat brain, although only limited quantitative data have been reported (Fake et al. 1987; Sanger & Nelson 1989). In rat and guinea-pig brain studies using 3H_ granisetron as a ligand, granisetron had a 4000 to 40000 times greater affinity for central 5-HTJ receptors than for other receptor types studied including opiod receptors (Blower 1990). Evidence to support that centrally located 5HTJ receptors are functional has been provided by studies in the rat. 5-HT3 receptor antagonists, including granisetron, have been shown to suppress medial prefrontal cortex (mPFc) cell firing rate, while the atypical antipsychotic agent clozapine antagonised the 2methyl serotonin induced suppression of mPFc cell firing (Ashby et al. 1989). In addition, the release of cerebral acetylcholine from terminals in the

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cerebral cortex appears to be regulated by 5-HT 3 receptors (Barnes et al. 1989a). 1.2 Antiemetic Effects The ferret is a suitable animal model for cytotoxic-induced emesis research since it exhibits a full behavioural representation of emesis. Ferrets show an acute emetic response to apomorphine (a dopamine 02 agonist), suggesting the presence of a chemoreceptor trigger zone, and a dose-related emetic response to cisplatin, which can be blocked by antiemetic agents (Florczyk et al. 1982). In addition, some researchers have subjectively characterised 'nausea' in the ferret to include events such as drinking, defecation, posturing to defecate, urgent burrowing, obtrusive licking and urgent backing movements which differed from control animals (Bermudez et al. 1988; Higgins et al. 1989). Data presented in the following section have been obtained using this model. Emesis was effectively reduced or abolished in all animals after a single dose of granisetron 0.5 rug/kg administered intravenously 30 minutes before cytotoxic drug administration, followed by a second identical dose of granisetron 45 minutes (for cisplatin) or 30 minutes (for doxorubicin and cyclophosphamide) after the cytotoxic agent (Bermudez et al. 1988; Boyle et al. 1987a,b). Granisetron in doses as low as 0.005 mg/kg intravenously x 2 doses (Bermudez et al. 1988;Boyle et al. 1987a, b), or single doses of 0.005 to 0.5 mg/kg intravenously or orally (Bermudez et al. 1988; Blower 1990), also provided protection against cisplatin-induced emesis. Subjective signs of nausea in cisplatintreated ferrets were reduced or eliminated by a single intravenous dose of granisetron 0.5 rug/kg (Bermudez et al. 1988). When compared with metoclopramide 2 doses of 2.5 rug/kg intravenously, granisetron 2 x 0.5 rug/kg intravenously was about 2 to 10 times more effective at reducing the number of emetic episodes evoked by doxorubicin and cyclophosphamide (Blower 1990; Boyle 1987a). For each emetogenic drug tested, a single intravenous dose ofgranisetron 0.5 mg/kg administered during an emetic episode abruptly terminated

vomiting within 15 to 60 seconds (Bermudez et al. 1988; Blower 1990; Boyle 1987a,b). Studies in the ferret also demonstrate the effectiveness of granisetron in prevention and treatment of radiation-induced emesis (Bermudez et al. 1988; Blower 1990; Boyle et al. 1987a,b). A single intravenous injection of granisetron 0.5 rug/kg administered 5 or 10 minutes before lO-minute exposure to an x-irradiation source, or 0.5 mg/kg given orally 60 minutes before exposure, completely prevented emesis in all animals (Bermudez et al. 1988; Boyle I987a,b). Intravenously administered granisetron 0.005 to 5 rug/kg also reduced or abolished emesis evoked by exposure to x-ray, and emesis was greatly reduced by an oral dose of granisetron 0.5 mg/kg administered 60 minutes prior to radiation exposure (Bermudez et al. 1988; Blower 1990; Boyle et al. I987a,b). Granisetron 0.005 to 5.0 mg/kg administered intravenously to ferrets 5 or 15 minutes before whole body x-irradiation of 300 rads/rnin for 10 minutes was significantly superior to placebo (Blower 1990; Boyle 1987b). This was measured by reductions in the number of emetic episodes and by prolongation of the latency period before vomiting occurred (Blower 1990; Boyle et al. 1987b), and by reduction in the number of emetic episodes in a 2-hour observation period (0 for granisetron vs 28.8 for placebo; p < 0.001) [Boyle et al. 1987b]. When granisetron 0.5 mg/kg was administered intravenously during an emetic episode induced by x-irradiation, vomiting was abolished within 15 to 30 seconds (Bermudez et al. 1988; Boyle et al. 1987a,b), indicating an onset of antiemetic effect similar to that seen with cytotoxic drug-induced emesis. 1.3 Mechanism of Action There is a paucity of basic research into the mechanisms by which cancer chemotherapy and radiation cause nausea and vomiting. The most widely favoured theory is that cytotoxic drugs and radiation cause cellular damage, eliciting the release of serotonin from enterochromaffin cells of intestinal mucosa (Andrews et al. 1988). This activates vagal and possibly splanchnic afferent neu-

Granisetron: A Review

Area postrema Nucleu s tractus soIitarius

811

Central nervous system

,. S·HT3 receptors

\

Granisetron

Vagal afferents

. Systemic circulation

Liver

Absorption

Gut wall

Granisetron~ Fig. 2. Proposed sites of action of granisetron at 5-HT3 receptors located on vagal afferent fibres and in or near the nucleus tractus solitarius and area postrema (adapted from Andrews et al. 1988).

rons and probably sensitises them to other stimuli , which in turn initiates the vomiting reflex (Andrews et al. 1988; Hawthorn et al. 1988; fig. 2). This hypothesis is supported by studies demonstrating marked increases in serotonin plasma concentrat ions in some patients (Barnes et al. 1990b) and significant increase in the mean urinary excretion of 5-hydroxyindoleacetic acid (Cubeddu et al. 1990),the main metabolite of serotonin, following cisplatin administration, which coincided with the presence of emesis. Abdominal visceral afferents are the main emetic detectors (Andrews et al. 1988); however, the nucleus of the tractus solitarius is rich in 5-HT3 binding sites, most of which are located on vagal afferents originating from the gut (Leslie et al. 1990; Pratt et al. 1990). The area postrema of the medulla oblongata appears to pos-

sess a lower concentration of 5-HT3 receptors (Pratt et al. 1990) which also likely receive visceral afferents from the gastrointestinal tract. These emetic detectors relay information to the vomiting centre which represents a complex interaction between the area postrema, nucleus tractus solitarius, parvicellular reticular formation , and visceral and somatic motor nuclei (Andrews et al. 1988; Pratt & Bowery 1989). The mechanism of action of granisetron and other 5-HT3 blockers in preventing nausea and vomiting induced by cancer chemotherapy and radiation is likely to involve antagonism of both peripheral and central 5-HT3 receptors (Andrews et al. 1988; Hawthorn et al. 1988; Higgins et al. 1989). Studies in the ferret suggest that antiemetic effects of 5-HT3 antagonists are mediated mainly by 5-HT3 receptors on vagal afferent terminals in the wall of the upper gut, with additional minor sites of action in the nucleus tractus solitarius or presynaptically on the vagal afferent terminals in the medulla (Andrews et al. 1990). In the cat, intracerebroventricular administration of cisplatin induced emesis; zacopride, a 5-HT3 antagonist, administered intracerebroventricularly or intravenously blocked the emetic response (Smith et al. 1988). Furthermore, injection of a 5-HT3 antagonist (GR 38032F, GR 65630A or MDL 72222) directly into the area postrema region of the ferret brain inhibited cisplatin-induced retching, vomiting and subjective signs of nausea compared with controls (Higgins et al. 1989). Together, these findings suggest that the antiemetic action of granisetron is mediated by antagonism of the actions of serotonin at 5-HT3 receptors on abdominal vagal afferents and in or near the chemoreceptor trigger zone. This hypothesis does not adequately address the possible reasons for the protracted duration of vomiting over several days which can occur with some cytotoxic drugs; however, it has been speculated that once 5-HT3 receptors in vagal afferents and in the area postrema are activated, they may remain sensitised for long periods (Andrews et al. 1988). It has been proposed that certain antiemetics , such as metoclopramide, may elicit some of their

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effects by stimulating gut motility which may reduce afferent activity in the vagus nerve (Alphin et al. 1986). In dogs, granisetron was shown to have virtually no gastrointestinal motor-stimulating activity in intravenous doses up to I mg/kg (Yoshida et al. 1991). A review of the prokinetic effects of ondansetron, another 5-HT 3 antagonist, revealed equivocal results suggesting that the effects of ondansetron on gastrointestinal motility are unlikely to be related to its antiemetic action (Milne & Heel 1991).

2. Pharmacokinetic Properties The pharmacokinetic properties of granisetron have been determined in healthy volunteers (Allen et al. 1990; Clarkson et al. 1988; Koyanagi et al. 1990; Kumakura et al. 1990; Upward et al. 1990; Zussman et al. 1988) and in cancer patients (Addelman et al. 1990; Carmichael et al. 1989), using high performance liquid chromatography following single-dose intravenous administration. All data thus pertain to the intravenous formulation. Oral bioavailability studies and data on plasma protein binding of granisetron in humans are not available. 2.1 Plasma Concentrations and Distribution After rapid intravenous administration of granisetron 20 or 40 ug/kg over 2 minutes to healthy volunteers, mean peak plasma concentrations achieved 5 minutes post dose were 13.7 and 42.8 /lg/L, respectively, and decreased bi-exponentially (Koyanagi et al. 1990). Mean peak plasma granisetron concentrations were higher (436 /lg/L) after a rapid 3-minute intravenous injection of granisetron 150 /lg/kg compared with intravenous administration over 30 minutes of the same dose (128 /lg/L); however, the higher values were only maintained for a matter of minutes due to rapid initial distribution of the drug to the tissues (Upward et al. 1990). Area under the plasma concentration-time curve (AUe) values also showed proportional increases with dose (30.1 /lg/L· h; 20 /lg/ kg dose vs 65.0 /lg/L· h; 40 /lg/kg dose), demonstrating essentially linear kinetics. This is consistent with other studies in healthy volunteers over a

50 40 ::J'

Oi 30 .=, x

~ 20

0

10 0 120 100 ': 80 ...J

~ 60

•

0

~ 40

20

•

•

O+-----r--.---.---,---,--.-----,-.---,---"l

o

~

~

~

W

100

Dose (ltg/kg)

Fig. 3. Relationship between peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AVC) to dose in 6 healthy volunteers administered granisetron 10 to 80 ltg/kg intravenously (after Kumakura et al. 1990).

wider dosage range (10 to 300 J,tg/kg) where plasma half-life, volume of distribution, total plasma clearance and renal clearance remained generally unchanged, while peak plasma concentrations and AUC values increased approximately in proportion to dose (fig. 3) [Allen et al. 1990; Kumakura et al. 1990]. Mean AUC values were higher in cancer patients (277 to 350 /lg/L· h; 40 /lg/kg dose) than in healthy volunteers (63 to 106 /lg/L· h; 40 /lg/kg dose) [table I]. Granisetron is widely distributed in healthy volunteers (mean volume of distribution 174 to 258L) [Allen et al. 1990; Kumakura et al. 1990; Zussman et al. 1988], and in cancer patients (2.2 to 3.3 Lzkg; 154 to 231L in a 70kg patient) [Addelman et al. 1990; Carmichael et al. 1989]. 2.2 Elimination The mean elimination half-lifein cancer patients receiving a single intravenous dose of 40 or 80 /lg/ kg is about 10 to 12 hours, as compared with

Granisetron: A Review

813

roughly 3 to 4 hours in healthy volunteers over a wide dosage range of 2.5 to 300 Jlg/kg (table I). Mean total body clearance in cancer patients is 0.21 to 0.48 L/h/kg [14.7 to 33.6 L/h in a 70kg patient] (Addelman et al. 1990;Carmichael et al. 1989), and 33.4 to 75.7 L/h in healthy volunteers (Allen et al. 1990; Kumakura et al. 1990). Further pharmacokinetic studies are required to determine whether these divergent findings in patients and healthy subjects reflect differences in drug elimination due to the underlying disease process, drug interactions with coadministered antineoplastic agents, changes in plasma protein binding (Addelman et al. 1990) and/or increased age of cancer patients relative to healthy volunteers, which appears to be associated with reduced clearance of ondansetron (Pritchard et al. 1990). As well, among individual volunteers and patients, there are wide inter-subject differences in plasma half-life and total plasma clearance with over lO-fold variability in some cases (Addelman et al. 1990; Carmichael et al. 1989; Upward et al. 1990; Zussman et al. 1988). Elimination is primarily by nonrenal mechan-

isms (Allen et al. 1990; Carmichael et al. 1989). In healthy volunteers 8 to 15% of a dose is recovered unchanged in the urine (Allen et al. 1990; Koyanagi et al. 1990). In addition, creatinine clearance values showed no relationship to granisetron clearance in cancer patients (Carmichaelet al. 1989). 2.3 Relationship Between Plasma Concentration and Clinical Efficacy Clinical trials show essentially equal antiemetic efficacy of granisetron over a wide range of intravenous dosages (see section 3). Nevertheless, one study of 18 cancer patients receiving a variety of antineoplastic agents demonstrated that those who achieved complete or good control over nausea and vomiting generally had higher plasma concentrations of granisetron than those who had a poor response. On an individual basis, however, there was no obvious threshold level for effect. In the same study, there was a statistically significant difference in mean plasma granisetron concentrations between responders (16.8 Jlg/L) and nonresponders

Table I. Comparison of mean elimination half-life (tl/2) and area under the plasma concentration-time curve (AUC) values of grani setron in healthy volunteers and cancer patients after administration of granisetron as a single intravenous dose Reference

Healthy volunteers Allen et al. (1990)

Number of subjects

6 4 8 7

Koyanagi et al. (1990a)

8 12 12

Kumakura et al. (1990)

Upward et al. (1990) Zussman et al. (1988) Cancer patients Addelman et at, (1990) Carmichael et al. (1989)

6 6 6 6 6 6 4 12 12 14

Dose (ltg/kg)

tl/2 (h)

30 40 50-130

3.9 4.0 5.5

150-230 270-300

4.5 5.9

20 40 10 20 40 80 2.5 30 40 40 80 40

3.1 3.2 3.4 4.3 3.1 2.3 3.9 3.9 4.0 11.6 9.8 10.6

AUC (ltg/L' h)

30.1 65.0 12.5 45.7 63.1 86.6 63.6 106 277 359 350

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Drugs 42 (5) 1991

Table II. Antiemetic efficacy as defined by the Granisetron Study Group (from Chevallier 1990; Pintens 1990; Soukop 1990) Complete responders

Patients who experience no vomiting and have mild or no nausea in the 24 hours after administration of antiemetic therapy

Major responders

Patients who experience only 1 episode of vomiting or retching or, if no vomiting, report moderate to severe nausea in the first 24 hours

Minor responders

Patients who vomit 2 to 4 times in the first 24 hours, regardless of nausea rating

Failures

Patients who vomit more than 4 times in the first 24 hours, regardless of nausea rating

(9.1 /lg/L) 5 hours after intravenous administration of granisetron 40 /lg/kg. AVC values were higher for responders compared with non responders (406 vs 193 /lg' h/L) , but this difference was not statistically significant (Carmichael et al. 1989).

3. Therapeutic Use 3.1 Cytotoxic Drug-Induced Nausea and Vomiting From the patient's perspective, nausea and vomiting are the most distressing treatment-related effects of cancer chemotherapy (Coates et al. 1983). These effects may last for several days, can lead to anticipatory nausea and vomiting and may ultimately result in the patient's refusal to continue effective antitumour therap y. Complications, such as dehydration, electrolyte imbalance, malnutrition and aspiration pneumonia, can also occur (Andrews et al. 1988; Joss et al. 1990). Metoclopramide is often the standard antiemetic against which other agents are compared. At conventional doses (10 to 20mg up to 3 times daily) metoclopramide acts as a dopamine D2 receptor antagonist and has limited antiemetic activity in patients receiving cancer chemotherapy, particularly cisplatin (Blower 1990; Moertel & Reitemeier 1969; Tabona 1990). At higher doses (e.g. 2 rug/kg), metoclopramide antagonises 5-HTJ receptors and provides a better antiemetic response (Blower 1990); however, as many as 30 to 60% of patients receiving high-dose cisplatin therapy (> 49 .mg/ m - ) will still experience some nausea and vomiting (Cupissol et al. 1990; Kris et

al. 1985; Monkovic 1989). The use of high-dose metoclopramide can be limited by the up to 5% incidence of extrapyramidal effects; this may be substantially higher in younger patients (Kris et al. 1983; Smith 1989). While antiemetic regimens combining high-dose metoclopramide with diphenhydramine, dexamethasone or other agents have reduced extrapyramidal effects and improved antiemetic control (Kris et al. 1985), more effective and well tolerated agents which obviate the need for polypharmacy are desirable. Even with combination therapy, emesis induced by high-dose cisplatin remains notoriously difficult to prevent or treat. A limited number of trials in patients receiving cisplatin chemotherapy have compared granisetron with placebo and with agents of established antiem etic efficacy, including metoclopramide. There are not yet any comparisons of the antiemetic efficacy of granisetron versus other potent and selective 5-HTJ receptor antagonists, nor has the effectivenessof granisetron in combination with dexamethasone or other antiemetic agents been investigated. However, findings of a study using ondansetron, another 5-HTJ receptor antagonist, with or without concomitant dexamethasone, indicate that such combined therapy may be beneficial (Roila et al. 1991). Cancer chemotherapeutic agents exhibit a wide range of emetogenic potential from severe (60 to 100% of patients experience emesis) with agents such as cisplatin and higher doses of cyclophosphamide, to low (0 to 30%) with agents such as asparaginase and methotrexate (Joss et al. 1990;

Granisetron: A Review

815

Triozzi & Laszlo 1987). When agents are combined, the emetogenic potential of each drug may be additive. In general, nausea and vomiting begin within the first 4 to 6 hours after administration of the chemotherapeutic agent, peak within 4 to 10 hours and subside by 12 to 24 hours, although the effects may persist, to a diminishing extent, for several days. When regimens involve several consecutive days of chemotherapy administration, nausea and vomiting may peak during the first 24 hours (or later), then gradually diminish (Triozzi & Laszlo 1987). Thus , most clinical trials of granisetron evaluated its antiemetic activity over 24 hours, with some examination of efficacy over 7 days. Studies often included patients receiving cisplatin as part of their chemotherapy regimens and, frequently , patients enrolled in these trials had not previously received chemotherapy (chemotherapynaive) to avoid the confounding factors of anticipatory nausea and vomiting. Definitions of antiemetic efficacy varied between studies; however, the most widely used terms were those defined by the Granisetron Study Group and are outlined in table II. All studies described in this section involved administration of granisetron as an intravenous formulation . 3.1.1 Dose-Finding Studies Double-blind studies undertaken to determine

the optimal antiemetic dose of granisetron in cancer patients have not shown significant differences between a single 40 or 160 Ilg/kg dose, usually administered 5 minutes prior to chemotherapy, with up to 2 supplemental doses of 40 Ilg/kg allowed within the first 24 hours (maximum total doses of 120 or 240 Ilg/kg, respectively) [table III]. This is demonstrated by the similar response rates achieved for all parameters measured: • complete response (57 to 76% of those treated with low dose vs 61 to 81% treated with high dose) • major efficacy, defined as 'complete plus major responders' (73 to 91% vs 74 to 92%) • number of patients requiring I or 2 supplemental doses (18 to 37% vs 15 to 33%) • number of patients in whom symptoms improved or resolved with a single supplemental dose (89 to 95% vs 85 to 91%) • global efficacy rated 'good or very good' after 24 hours (76 to 81% vs 77 to 91%) • global efficacy rated 'good or very good' after 7 days (71 to 81% vs 72 to 86%) The antiemetic efficacy of granisetron did not vary according to the primary cytostatic agents of the chemotherapy regimens administered to patients, which included cisplatin (Smith 1990; Soukop 1990). These findings suggest that 40 ug/ kg is the most appropriate dose for preventing cytotoxic drug-induced emesis. Additional data

Table III. Summary of double-blind , parallel dose-finding studies investigating the use of intravenous granisetron in cancer patients undergoing chemotherapy Reference

No. of patients

DoseS (I'g/kg)

Falkson et al. (1990) Smith (1990) Soukop (1990)

a b c No

28 28 223 220 149 147

40 160 40 160 40 160

Patients with complete response?

Patients with major efficacyC

(%)

(%)

71 79 76 81 57 61

91 92 73 74

Patients were allowed up to 2 additional 40 I'g/kg doses of granisetron for breakthrough symptoms during the first 24 hours . Definition as outlined in table II. Complete response plus major response as defined in table II. statistically significant differences between groups were found in any study.

816

from patients with malignant disease who received granisetron prior.to cisplatin ~ 75 mg/m 2 showed a clear reduction in efficacy below 10 ILg/kg, and optimal dosing at 40 ILg/kg (data on file, SmithKline Beecham). Together, these findings allow a more universal and simplified regimen independent of bodyweight (see section 5). Preliminary data in children suggest that 20 or 40 ILgfkg, administered in a single dose prior to chemotherapy, is well tolerated and provides good efficacy over at least 24 hours (Lemerle et a1. 1991).

3.1.2 Comparisons With Placebo Highly emetogenic cytotoxic drugs are not suitable for placebo-controlled antiemetic studies since it is unethical to withhold antiemetic agents in these patients. Consequently, the antiemetic activity of granisetron has not been extensively compared with placebo. However, in addition to demonstrating the efficacy of granisetron in preventing cytotoxic druginduced emesis, these trials can provide insight into the effectiveness of granisetron as an intervention agent (antiemetic 'rescue' treatment), since the drug is also administered to patients in the placebo groups after vomiting has begun. Placebo-controlled trials clearly demonstrated that granisetron was significantly superior to placebo in preventing emesis induced by cisplatin (> 50 mg/m-') with or without other chemotherapeutic agents (table IV). In addition, once vomiting occurred in patients who were administered placebo, granisetron was very effective as an intervention agent, usually abolishing emesis within a few minutes after its administration. Complete response was obtained in 93% (13/14) of chemotherapy-naive patients administered granisetron, compared with 7% (1/14) of placebo recipients (p < 0.001) [Cupissol et a1. 1990] and, in a larger trial , emesis was absent in 67% (56/83) of patients receiving granisetron compared with 10% (8/82) receiving placebo (p < 0.01) [Furue et a1. 1990]. Time to the first episode of vomiting was significantly longer (p < 0.001) in the granisetron group studied by Cupissol et al (1990). All patients in the placebo group who required

Drugs 42 (5) /99/

' rescue' therapy with up to 3 doses of granisetron 40 ILg/kg (n = 13) showed resolution (n = 9) or improvement (n = 4) of symptoms within minutes of administration, as did the 'small number' (not specified) of patients in the granisetron group who required supplementary doses of granisetron 40 ILg/ kg for breakthrough symptoms. After 24 hours, therapy was rated as either 'good or very good' by 13 of 14 of patients treated with granisetron versus 3 of 14 placebo recipients (Cupissol et a1. 1990). Results were again similar in the larger trial. Of those patients who experienced ineffective prophylaxis of cytotoxic drug-induced emesis with placebo administration (n = 64), intervention therapy with granisetron was deemed to be 'effective' in over 90% (58/64) , while a second dose of granisetron 40 ILg/kg administered to patients unresponsive to the initial prophylactic dose of granisetron (n = 11) provided 'effective' therapy in about 40% (4/ II) of patients (Furue et a1. 1990).

3.1.3 Comparisons With Other Antiemetic Agents Metoclopramide is often a standard component of antiemetic therapy in patients receiving cancer chemotherapy. Unfortunately, administration of high-dose metoclopramide is associated with the development of extrapyramidal effects and emesis remains uncontrolled in man y patients receiving cisplatin. When combined with other agents such as dexamethasone and diphenhydramine, the antiemetic efficacy of metoclopramide can be improved (Kris et al. 1985; Sridhar & Donnelly 1988); however, a need exists for an effective single antiemetic regimen devoid of extrapyramidal or other side effects. In the limited number of clinical trials comparing granisetron with other antiemetic agents in relativel y large numbers of patients receiving chemotherapy, granisetron was at least as effective as a combination of high-dose intravenous metoclopramide plus intravenous dexamethasone, with or without diphenhydramine, and was superior to a combined regimen of parenteral and oral chlorpromazine plus intravenous dexamethasone, or a combination of prochlorperazine and dexam etha-

817

Granisetron: A Review

Table IV. Comparisons of the antiemetic effects of granisetron (G) with placebo (P) and other antiemetic regimens in patients receiving cancer chemotherapy Reference

Number of evaluable

Chemotherapy

Study design

(mg/m 2)

patients

Antiemet ic regimen

Patients with no emesis in first 24

(lLg/kg)

hours (%)

Placebo Cupissol et al. (1990) Furue et al. (1990) Other antiemetic regimens Breme r et al.

14 14

CIS

83 82

CIS ~ 50 (+ others)

~

r, db,

50

pa me, r, db, pa

G 40 P G 40 P

93b " 7b 67" 10

99 87 114

CIS ~ 15 or ETO or IFO CIS ~ 49

me, r, sb, pa me, r,

G 40 A+D G 40

556 446 70b

(1990) Marty

120

(+ others)

115

sb, pa me, r,

M+D G 40

(1990) Niitani et al.

113 37 37 74 75 76 76

CAR and/or CIS 20-50 and/or others

sb, pa me, r, nb, co r, db

C+D G 40

69b 70b" 49b

(1990) Chevallier

(1990) Venner et al. (1990) Warr (1989) a b

CIS 80 and VIN and MIT CIS > 49 CIS

< 50

r, db

ME G 80 MDD G 80 PR + D

59" 19 46 44 70" 34

Efficacy assessed using 'complete response ', as outlined in table II, over 5 days. Efficacy assessed using 'complete response ', as outlined in table II.

=

=

multicentre; r random ised; sb = single-blind; db = double-blind; nb = nonblind ; pa = parallel; co = crossover; CAR = carboplatin; CIS = cisplatin ; ETO = etoposide; IFO = ifosfam ide; MIT = mitomycin ; VIN = vindesine; IV = intravenously; 1M = intramuscularly; A + D = alizapride 4 mg/kg IV every 4 hours x 3 doses + dexamethasone 8mg IV daily; M + D = metoclopramide 3 mg/kg IV loading dose , then 4 mg/kg IV over 8h + dexamethasone 12mg IV; C + D = chlorpromazine 25mg IV/1M with additional oral doses + dexamethasone 12mg IV; ME = methylprednisolone 500mg IV; MDD = metoclopramide 2 mg/kg IV every 2h x 5 doses plus dexamethasone 10mg IV and diphenhydramine 50mg IV; PR + D = prochlorperazine plus dexamethasone (no further details available). Symbol: " = statist ically significant difference vs comparator treatment (p value at least < 0.01).

Abbreviations: mc

sone, or high-dose methylprednisolone monotherapy (table IV). The antiemetic efficacy of granisetron 40 J,tg/kg (n = 114), administered 5 minutes prior to chemo therapy, was compared with a combination of highdose metoclopramide (3 rug/kg loading dose, then 4 mg/kg over 8 hours) plus intravenous dexamethasone 12mg (n = 120) in a large multicentre, single-blind study of 234 patients (230 chemotherapy-naive). All patients received cisplatin, and in all but 6 cases the dose was > 49 mg/m-', 13 patients received additional antineoplastic therapy. Patients in the granisetron group were allowed up to 2 supplemental doses of granisetron 40 J,tg/kg for break-

through nausea and vomiting during the 24 hours after cytotoxic administration. The results of this study demonstrate that granisetron is at least as effective as the metoclopramide/dexamethasone combination during the first 24 hours after chemotherapy administration. Although granisetron tended to be better in a few parameters, none of the differences in antiemetic efficacy between the 2 treatment groups were statistically significant (fig. 4). Complete response over 24 hours was obtained in 70% of patients receiving granisetron compared to 69% of the comparator group. There was also no statistically significant difference in the antiemetic efficacy over 7 days, with 33% of patients

Drugs 42 (5) 1991

818

Percentage 01 pat.ents

o

10

20

30

40

50

60

70

80

90 100

Major responders over 24h

Major effICaCy (complete plus major responders ) over 24h

Minor responders over 24h

Fa~ures

• Granisetron

o MetocJopramide + dexamethasone

over 24h

Global efficacy rated as 'good' or 'very good ' by pat.ents after 24h

Complete response over 7 days

Fig. 4. Comparison of the antiemetic efficacy of granisetron 40 to 120 I'gjkg (n = 114) with metoclopramide 7 mgjkg plus dexamethasone 12mg (n = 120) in patients receiving highdose cisplatin therapy (after Chevallier 1990), All drugs were administered intravenously. Differences between groups were not statistically significant. Parameters are defined in table II,

in the granisetron group and 51% of patients receiving metoclopramide obtaining a complete response over this period (Chevallier 1990). The antiemetic efficacy of granisetron compared with metoclopramide was similar in another study in patients receiving cisplatin > 49 mg/m 2• Granisetron 80 JIg/kg (n = 74) completely prevented emesis for 24 hours after chemotherapy administration in 46% of patients compared to 44% of those who receiving metoclopramide 2 mg/kg intravenously every 2 hours for 5 doses in conjunction with intravenous administration of dexa-

methasone lOmg and diphenhydramine 50mg (n = 75) [Venner et al. 1990]. There is also some evidence that granisetron may be useful as rescue medication in nonresponders to low doses of metoclopramide. In a multicentre, nonblind trial of 20 patients receiving cisplatin > 50 mg/m 2 with or without other cytotoxic agents, a single intravenous dose of metoclopramide 20mg did not prevent nausea and vomiting in 18 of 20 patients. Of those requiring rescue therapy with a single dose of granisetron 40 JIg/kg, 13 of 18 did not vomit in the 24 hours following administration, and the global efficacy of granisetron was rated as 'good or excellent' in 15 of 18 patients (Machida et al. 1990). Further studies have evaluated the antiemetic activity of granisetron relative to that of agents other than metoclopramide.One large, single-blind, parallel, multicentre study of 228 patients (216 chemotherapy-naive) who received a variety of chemotherapeutic regimens of moderately severe emetogenic potential , compared the antiemetic activity of granisetron 40 JIg/kg with a combination of dexamethasone 12mg intravenously plus chlorpromazine 25mg intravenously or intramuscularly, each administered just prior to chemotherapy. Patients in the granisetron group (n = 115) were allowed up to 2 additional 40 JIg/kg doses within the first 24 hours to control breakthrough symptoms, while those in the comparator group (n = 113) could receive chlorpromazine orally every 4 to 6 hours to a maximum dosage of 200mg during the first 24 hours of the study. Significantly more patients in the granisetron group showed a complete response over 24 hours (70% vs 49%) or 7 days (50% vs 36%), and the incidence of nausea and vomiting tended to be less frequent within 12, and 24 hours compared with the group receiving the dexamethasone/chlorpromazine regimen (fig. 5). The efficacy of granisetron did not vary with the type of chemotherapeutic regimen administered (Marty 1990). A small subset of patients (n = 39) completed a crossover trial with these antiemetic agents and 82% of patients expressed a preference for granisetron (M Marty, personal communication).

819

Granisetron: A Review

Percentage of patients 01020304050607080

Complete

respoooers (over 24h)

*

Complete

respoooees

(over 7 days) • Gran,setron Onset of

vomitong

o Dexamethasone chlorpromaZIne

+

within 12h

Onset of

nausea

within 12h

Onset of

\lomiting

within 24h

Onset 01

nausea within 24h

Fig. 5. Comparison of the antiemetic activity of granisetron 40 to 120 I'gjkg (n = 115) with dexamethason e 12mg intravenously plus chlorpromazine 25mg intravenously or intramuscularly (n = 113) in patients receiving chemotherapy of similar emetogenic potential (after Marty 1990). Statistically significant difference between treatment groups: * p ".; 0.01; ** P ".; 0.001.

Similar superior effects have been shown for granisetron when compared with methylprednisolone or with a combination of prochlorperazine plus dexamethasone. In a multicentre study, 37 patients receiving a chemotherapeutic regimen containing cisplatin 80 mg/m-', vindesine 3 mg/m? and mitomycin 7 to 8 mg/m 2 were administered a single dose of granisetron 40 Jig/kg or methylprednisolone 500mg in a crossover manner, prior to successive chemotherapy cycles. The global efficacy of granisetron was rated as 'useful or very useful' in 81% (30/37) of patients compared with 35% (13/ 37) for methylprednisolone (p < 0.01). Significantly more patients who received granisetron experienced no vomiting during the study period

compared to those who received methylprednisolone (59% vs 19%) [Niitani et al. 1990]. Granisetron 80 Jig/kg (n = 76) administered to cancer patients prior to non-cisplatin-based chemotherapy (usually doxorubicin combinations) completely prevented emesis in 70% of patients during the initial 24 hours compared to 34% of those receiving prochlorperazine plus dexamethasone (n = 76) [Warr 1989]. In a large single-blind multi centre trial cancer patients received cisplatin > IS mg/m 2/day, etoposide > 120 mg/m 2/day or ifosfamide > 1.2 g/ m 2/day for 5 consecutive days. Patients were randomly assigned to antiemetic therapy with granisetron 40 Jig/kg administered prior to chemotherapy on each day with up to 2 additional doses per day allowed for breakthrough symptoms (n = 99) or alizapride 4 mg/kg and dexamethasone 8mg administered intravenously daily prior to antineoplastic administration, followed by 2 further doses at 4 and 8 hours after chemotherapy. There was a tendency for more patients treated with granisetron to be completely without emesis during the 5day study period (55%) compared with those who received intravenous alizapride and dexamethasone (44%) [Bremer et al. 1990]. 3.2 Radiation-Induced Nausea and Vomiting The severity of radiation-induced emesis can vary substantially and is related to the site and dose rate of radiation. It is generally less intense than aggressive cytotoxic drug-induced vomiting, but can last throughout weeks of radiation therapy if untreated (Priestman 1989). Total body irradiation delivered as a single fraction at a fast dose rate to a total dose of approximately 750 cGy can be expected to consistently induce emesis in more than 95% patients, despite the use of combination antiemetic therapy with metoclopramide 5 to IOmg, dexamethasone 6 mg/rn-" and phenobarbitone 60 mg/m 2 administered I hour before radiation (Prentice 1991). Although evidence from animal models demonstrates an excellent antiemetic effect of granisetron in preventing radiation-induced nausea and vomiting (section 1.2), there are lim-

820

ited data on this use in humans. Of 32 patients . receiving granisetron 40 ug/kg who were subjected to total body irradiation in an non blind, noncomparative trial , 56% did not experience emesis or nausea during the initial 24 hours while only 19% of patients reported emesis during the next 6 days. Less than 10% of patients required more than a single dose of granisetron (Hunter et al. 1991; Prentice 1991).

4. Tolerability Determining the tolerability profile of an antiemetic agent used in chemotherapy is difficult since clinical trials also involve coadministration of cytotoxic agents which can produce adverse events as well. In most clinical trials, granisetron was well tolerated (Chevalier 1990; Cupissol et al. 1990; Marty 1990; Smith 1990; Soukop 1990). Extrapyramidal effects, which are an important concern with antiemetic regimens that include high-dose metoclopramide (Kris et al. 1983; Smith 1989; Triozzi & Laszlo 1987), have not been reported by any patients treated with granisetron. Headache was the most common adverse event observed in most larger studies, occurring in about to to 15% of patients (table V). Other less frequent undesirable events during granisetron treatment include constipation (0 to 4%), somnolence (0 to 3%) and diarrhoea (0 to 3%). Transient changes in blood pressure have also been detected in up to 8% of patients (table V), but these resolved without treatment in all cases and were generally considered to be clinically insignificant. The tolerability of granisetron does not appear to be dose -related since several studies, involving single or multiple intravenous doses totalling 20 to 240 /-Lg/kg/24h, have shown no significant differences in the incidence of adverse events when patients or volunteers were administered 2 different regimens of granisetron (Addelman et al. 1990; Falkson et al. 1990; Koyanagi et al. 1990; Smith 1990; Soukop 1990). However, one trial evaluating administration of intravenous granisetron in single ascending doses of 2.5 to 300 /-Lg/kg in 8 volunteers indicated that constipation only occurred at doses

Drugs 42 (5) 1991

of 80 ug/kg or higher, with an incidence of 50% at 300 /-Lg/kg although statistical analysis was not provided. Compared with placebo, a small, but statisticall y significant (p < 0.05) transient decrease in diastolic blood pressure after granisetron 300 /-Lg/ kg as a single intravenous dose was not considered clinically significant (Upward et al. 1990). Granisetron does not appear to impair psychometric performance, including subjective assessment of lethargy and objective variables such as reaction times and rapid information processing, and may be coadministered with lorazepam with no synergistic undesirable effects (Leigh et al. 1991). Elevated levels of the liver enzymes AST and ALT were reported with granisetron administration; however, other causes such as liver metastasis, fever or cytotoxic drug administration were implicated (Addelman et al. 1990).

5. Dosage and Administration The efficacy of granisetron is not reduced at doses of 40 /-Lg/kg and there is no increase in the number or severity of adverse events at doses of 240 /-Lg/kg (see sections 3 and 4). Furthermore, results of dose-finding studies have demonstrated that 40 /-Lg/kg is the optimal dose and efficacy is clearly compromised below 10 /-Lg/kg (section 3.1). On the basis of these data, the manufacturer has simplified the dosage regimen to a standard fixed 3mg dose infused over 5 minutes. Clinical studies have not yet been published using this fixed dosage regimen for all patients; however, from a practical viewpoint, single-dose administration in a simplified regimen over a short period provides the care-giver with an attractive alternative to other, often more complicated, regimens involving metoclopramide, with or without other agents. The most frequently employed dosage regimen in clinical trials, including those performed by the Granisetron Study Group, has been a single dose of 40 to 160 /-Lg/kg administered prior to chemotherapy, with 2 supplemental doses of 40 /-Lg/kg allowed within the first 24 hours after chemotherapy administration (section 3). The initial dose has generally been infused over 5 or 30 minutes, di-

Granisetron: A Review

821

Table V. Incidence of adverse events in cancer patients followi ng intravenous administration of granisetron (G) 40 to 240 I' g/k g and chemotherapy Adverse event

Incidence (% of patients) dose-fin ding studies

comparative studies Chevalier (1990)

G

ca

[n = 1141 Reported 1 or more adverse event Headache Transient changes in blood pre ssure Constipation Somnolence Diarrhoea Dizziness Flatulence

Marty (1990)

a b

Soukop et

al. (1990)

al. (1990)

G

Cb

[n = 1201

[n = 1151

[n = 1131

[n = 4431

[n

26

33

23"

35

30

31

11·

3 4

14 3

6 4

14

8

15 1

4 2

3

1

1

4

1 3

5

O·

16

8

= 296]

4

2 2 2

Dyspepsia Dry mouth Extrapyram idal effects

Smith et

0' ·

o

11

o

Comparator antiemetic regimen of dexamethasone 12mg IV + metoclopramide 7 mg/kg IV. Comparator antiemetic regimen of dexamethas one 12mg IV + chlorpromazine (CPZ) 25mg IV or 1Mwith supplemental oral doses

of CPZ to a maximum dose of 200mg within 24h. Abbreviation and Symbols: C = comparator antiemetic regimen; " = p ,,; 0.05; "" = P

luted in normal saline and completed 5 minutes before cisplatin or other chemotherapy administrat ion begins. In a few studies involving healthy volunteers, granisetron was administered more rapidly, over only 2 or 3 minutes , without any untoward effects (Koyanagi et al. 1990; Leigh et al. 1991 ; Upward et al. 1990).

6. Place of Granisetron in Antiemetic Therapy Nausea and vomiting evoked by cancer chemotherapy can not only lead to complications such as dehydration and electrolyte imbalance, but may cause enough anguish to result in the patient's refusal of any further potentiall y beneficial antineoplastic therap y. Despite the importance of this problem, it was only a decade ago that reasonable success was achieved in preventing cisplatin-induced emesis by using high doses of intra venous

< 0.01 vs

C.

metoclopramide (Gralla et al. 1981). However, administration of high-dose metoclopramide is associated with an incidence of extrapyramidal effects of up to 5% (Kris et al. 1983; Smith 1989), and as many as 30 to 60% of patients continue to experience nausea and vomiting with high-dose cisplatin therapy despite metoclopramide treatment (Cupissol et al. 1990; Kris et al. 1985; Monkovic 1989). Although the antiemetic efficacy of metoclopramide has been improved and the incidence of extrapyramidal effects reduced by coadministration with other drugs, the continuing search for more effective and better tolerated antiemetic agents has led to development of a novel group of agents known as 5-HT3 receptor antagonists, which includes granisetron. As might be expected at this early stage there are few published studies comparing the antiemetic efficacy of granisetron with other antiemetics, particularly high-dose metoclopramide; however, pre-

822

liminary findings are very promising. In large comparative trials, intravenous administration of granisetron prior to highly emetogenic chemotherapeutic regimens completely prevented emesis in 70% of cancer patients during the initial 24 hours following antineoplastic administration. Granisetron has been shown to be significantly superior to placebo, a combination of dexamethasone plus chlorpromazine, dexamethasone plus prochlorperazine, or single dose administration of methylprednisolone, and at least as effective over the first 24 hours as a regimen of intravenous high-dose metoclopramide plus dexamethasone, with or without diphenhydramine. Similarly, limited data comparing the antiemetic efficacy of granisetron with metoclopramide/dexarnethasone, dexamethasone/chlorpromazine, or dexamethasone/alizapride over 7 days following cancer chemotherapy suggest equivalent efficacy in preventing the delayed emesis which can occur after 24 hours, although wider clinical experience is required to verify this. Other areas deserving of further attention include comparisons with other 5-HT3 receptor antagonists such as ondansetron, and investigations of the coadministration of granisetron plus dexamethasone, an approach which has augmented the response to ondansetron. Also, the excellent antiemetic activity of granisetron in preventing radiation-induced emesis in the ferret and the preliminary data available in humans provides the basis for further clinical trials in this area. Granisetron is well tolerated, with few adverse effects on the central nervous system and no extrapyramidal effects reported to date. It appears that younger adults are the group most likely to exhibit extrapyramidal effects with high-dose metoclopramide administration (Kris et aI. 1983), while elderly patients poorly tolerate this adverse event (Salzman 1982), and consequently granisetron may prove to be particularly valuable in such patient groups. In summary, granisetron is an effective antiemetic agent in the prevention of nausea and vomiting associated with cancer chemotherapy. It is at least as effective over the first 24 hours after cancer chemotherapy as antiemetic combinations includ-

Drugs 42 (5) 1991

ing high-dose metoc1opramide, but unlike metoclopramide, holds no apparent risk of extrapyramidal effects. While certain aspects of its clinical profile require clarification, as a member of a novel class of drugs, the 5-HT3 receptor antagonists, granisetron plays a significant role in the advance of effective therapeutic control over cytotoxic-induced nausea and vomiting.

References Addelman M, Erlichman C, Fine S, Warr D, Murray C. Phase II II trial of granisetron: a novel 5-hydroxytryptamine antagonist for the prevention of chemotherapy-induced nausea and vomiting. Journal of Clinical Oncology 8: 337-341,1990 Allen A, Asgill CC, Pierce DM, Upward JW , Zussman BD. Pharmacokinetics of ascending intravenous doses of granisetron, a novel 5-HT 3-receptor antagonist. British Journal of Clinical Pharmacology 29: 619P-620P, 1990 Alphin RS, Proakis AG, Leonard CA, Smith WL, Dannenburg WN, et al. Antagonism of cisplatin-induced emesis by metoclopramide and dazopride through enhancement ofgastric motility . Digestive Diseases and Sciences 31: 524-529, 1986 Andrews PLR, Rapeport WG, Sanger GJ. Neuropharmacology of emesis induced by anti-cancer therapy. Trends in Pharmacological Sciences 9 (9): 334-341, 1988 Andrews PLR , Davis CJ, Bingham S, Davidson HIM , Hawthorn J, et al. The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Canadian Journal of Physiology and Pharmacology 68: 325-345, 1990 Ashby Jr CR , Edwards E, Harkins KL, Wang RY. Differential effect of typical and atypical antipsychotic drugs on the suppressant action of 2-methylserotonin on medial prefrontal cortical cells: a microiontophoretic study . European Journal of Pharmacology 166: 583-584, 1989 Barnes JM, Barnes NM , Cooper S. Behavioural pharmacology of 5-HT3 receptor ligands. Neuroscience and Biobehavioral Reviews, In press, 1991 Barnes JM, Barnes NM , Costall B, Deakin JFW , Ironside JW, et al. Identification and distribution of 5-HT3 recognition sites within the human brainstem. Neuroscience Letters III: 80-86, I990a Barnes JM , Barnes NM , Costall B, Ironside JW, Naylor RJ. Identification and characterisation of 5-hydroxytryptamine3 recognition sites in human brain tissue. Journal of Neurochemistry 53: 1787-1793, 1989b Barnes JM, Barnes NM, Costall B, Naylor RJ, Tyers MB. 5-HT3 receptors mediate inhibition of acetylcholine release in cortical tissue . Nature 338: 762-763, 1989a Barnes NM, Costall B, Naylor RJ, Tattersall FD . Identification of 5-HT3 recognition sites in the ferret area postrema. Journal of Pharmacy and Pharmacology 40: 586-588, 1988 Barnes NM, Ge J, Jones WG, Naylor RJ , Rudd JA. Cisplatin induced emesis : preliminary results indicative of changes in plasma levels of 5-hydroxytryptamine. British Journal of Cancer 62: 862-864, 1990 Bermudez J, Boyle EA, Miner WD, Sanger GJ . The anti-emetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694. British Journal of Cancer 58: 644-650, 1988 Blower PR o The role of specific 5-HT3 receptor antagonism in the control of cytostatic drug-induced emesis . European Journal of Cancer 26 (Suppl. I): S8-S II , 1990 Boyle EA, Miner WD, Sanger GJ . Anti-emetic activity of BRL

Granisetron: A Review

43694, a novel 5HT 3-receptor antagonist. British Journal of Cancer 56 (2): 227, 1987a Boyle EA, Miner WD, Sanger GJ. Different anti-cancer therapies evoke emesis by mechanisms that can be blocked by the 5HT3 receptor antagonist BRL 43694. British Journal of Pharmacolog y 91 (Suppl.): 418P, 1987b Bradley PB, Engel G, Feniuk W, Fozard JR , Humphrey PA, et al. Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacology 25 (6): 563-576, 1986 Bremer K, Smit P, on behalf of the Granisetron Study Group. Granisetron compared to a combin ation of abizapride plus dexamethasone for the prophylaxis and control of cytotoxic induced emesis over 5 days. Annals of Oncology I (Suppl.): 109, 1990 Buchheit K-H, Engel G, Mutschler E, Richardson B. Stud y of the contractile effect of 5-hydroxytryptamine (5-HT) in the isolated longitudinal muscle strip from guinea-pig ileum. Naunyn-Schmiedeberg's Archives of Pharmacology 329: 36-41, 1985 Carmichael J, Cantwell BMJ, Edwards CM, Zussman BD, Thompson S, et al. A pharmacokinetic stud y of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response. Cancer Chemotherapy and Pharmacology 24: 45-49, 1989 Chevallier B, on behalf of the Granisetron Study Group. Efficacy and safety of granisetron compared with high-dose metoclopramide plus dexamethasone in patients receiving high-dose cisplatin in a single-blind study . European Journal of Cancer 26 (Suppl. I): 33-36, 1990 Clarkson A, Coates PE, Zussman BD. A specific h.p.l.c. method for the determination of BRL 43694 in plasma and urine . British Journal of Clinical Pharmacology 25 (I) : 136P, 1988 Coates A, Abraham S, Kaye SB, Sowerbutts T, Frewin C, et al. On the receiving end - patient perception of the side-effects of cancer chemotherapy. European Journal of Cancer and Clinical Oncology 19 (2): 203-208, 1983 Couturier EGM, Hering R, Foster CA, Steiner Tl , Rose FC First clinical stud y of the selective 5-HT3 antagonist, granisetron (BRL 43694), in the acute treatment of migraine headache. Headache 31: 296-297,1991 Cubeddu LX, Hoffmann IS, Fuenmayor NT, Finn AL. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. New England Journal of Medicine 322: 810-816, 1990 Cupissol DR, Serrou B, Caubel M. The efficacy of granisetron as a prophylactic antiemetic and intervention agent in high-dose cisplatin-induced emesis. European Journal of Cancer 26 (Suppl. I): 23-27, 1990 Elliott P, Seemungal BM, Wallis OJ. Antagonism of the effects of 5-hydroxytryptamine on the rabbit isolated vagus nerve by BRL 43694 and metoclopramide. Naunyn-Schmiedebergs Archives of Pharmacology 341: 503-509, 1990 Fake CS, King FD, Sanger GJ . BRL 43694: a potent and novel 5-HT3 receptor antagonist. British Journal of Pharmacology 91: 335P, 1987 Falkson HC, Falkson CI, Falkson G. High versus low dose granisetron, a selective 5HT3 antagonist, for the prevention of chemotherapy-induced nausea and vomiting. Investigational New Drugs 8: 407-409, 1990 Florczyk AP, Schurig JE, Bradner WT. Cisplatin-induced emesis in the ferret: a new animal model. Cancer Treatment Reports 66 (I) : 187-189, 1982 Fozard JR, Mobarok Ali ATM , Newgrosh G. Blockade of serotonin receptors on autonomic neurones by (-) cocaine and some related compounds. European Journal of Pharmacology 59: 195-210, 1979 Furue H, Oota K, Taguchi T, Niitani H, Ogawa N. Clinical evaluation of granisetron against nausea and vomiting induced by

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anticancer drugs. II. Multicentred, placebo-controlled, doubleblind comparative study. Rinsho Iyaku 6(Suppl. 5): 63-86, 1990 Gralla RJ, Itri LM, Pisko SE, Squillante AE, Kelsen DP, et al, Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. New England Journal of Medicine 305: 905-909, 1981 Hawthorn J, Ostler KJ, Andrews PLR. The role of the abdominal visceral innervation and 5-hydroxytryptamine M-receptors in vomiting induced by the cytotoxic drugs cyclophosphamide and cis-platin in the ferret. Quarterly Journal of Experimental Physiology 73: 7-21, 1988 Higgins GA, Kilpatrick GJ, Bunce KT, Jones BJ, Tyers MB. 5HT3 Receptor antagonists injected into the area postrema inhibit cisplatin- induced emesis in the ferret. British Journal of Pharmacology 97: 247-255, 1989 Hunter AE, Prentice HG, Pothecary K, Coumar A, Collis C, et a!. Granisetron, a selective 5-HT3 receptor antagon ist, for the prevention of radiation induced emesis during total body irradiation. Bone Marrow Transplantation 7: 439-441, 1991 Ireland SJ, Tyers MB. Pharmacological characterization of 5-hydroxytryptamine-induced depolarization of the rat isolated vagus nerve. British Journal of Pharmacology 90: 229-238, 1987 Jones B. 5-HT 3 Receptor antagonists in anxiety and schizophrenia. Drug News and Perspectives 3 (2): 106-111 , 1990 Joss RA, Brand BC, Buser KS, Cerny T. The symptomatic control of cytostatic drug-induced emesis. A recent history and review. European Journal of Cancer 26 (Suppl. I) : S2-S8, 1990 Kilpatrick GJ, Jones BJ, Tyers MB. Binding of the 5-HT3Iignad, [3H)GR65630, to rat area postrema, vagus nerve and the brains of several species. European Journal of Pharmacology 159: 157164, 1989 Kilpatrick GJ, Jones BJ, Tyers MB. Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature 330: 746-748, 1987 King FD, Sanger GJ. 5-HT3 Receptor antagonists. Drugs of the Future 14 (9): 875-889, 1989 Koyanagi J, Kumakura H, Nishioka Y, Sato M, Nakajim a T, et al. A phase I study of granisetron (third report) - safety and pharmacokinetics of granisetron following 2-minute single intravenous injection in Japanese healthy volunteers . Rinsho Iyaku 6 (Suppl. 5): 35-47, 1990 Kris MG, Gralla RJ, Tyson LB, Clark RA, Kelsen DP, et al. Improved control of cisplatin-induced emesis with high-dose metoclopramide and with combinations of metoclopramide, dexamethasone, and diphenhydramine. Cancer 55: 527-534, 1985 Kris MG, Leslie B, Tyson LB, Gralla RJ, Clark RA, et al. Extrapyramidal reactions with high-dose metoclopramide. Correspondence. New England Journal of Medicine 309 (7): 433, 1983 Kumakura H, Koyanagi J, Nishioka Y, Sato M, Nakajima T, et al. Phase I study of granisetron (second report) - pharmacokinetics of granisetron following single and repeat intravenous drip infusion in Japanese healthy volunteers . Rinsho Iyaku 6 (Suppl. 5): 25-34, 1990 Leigh TJ , Link CGG, Fell GL. Effects of granisetron and lorazepam , alone and in combination, on psychometric performance. British Journal of Clinical Pharmacology 31: 333-336, 1991 Lemerle J, Lartigan E, Godzinski J, McDowel H, Upward J, et al. Efficacy and safety of granisetron in the prevention of chemotherapy induced emesis in children . Abstract . Medical and Pediatric Oncology 19: 420, 1991 Leonhardt S, Herrick-Davis K, Titeler M. Detection of a novel serotonin receptor subtype (5-HTIE) in human brain : interaction with a GTP-binding protein . Journal of Neurochemistry 53: 465-471, 1989 Leslie RA. Neuroactive substances in the dorsal vagal complex

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of the medu lla oblongata: nucleus of the tractus solitari us, area postrema, and dorsal motor nucleus of the vagus. Neuroc hemistry International 7: 191-21I, 1985 Leslie RA, Reynolds DJ M, Andrews PLR, Graharne-Smith DG, Davis 0 , et al. Evidence for presynaptic 5-hydroxytryptamine3 recognition sites on vagal afferent terminals in the brainstem of the ferret. Neuroscience 38: 667-673, 1990 Machida T, Masuda F, Onodera S, Kodera S. Clinical evaluatio n of granisetro n against nausea and vomiting induced by anticancer drugs IV - study on usefulness of metoclo prami de and granisetron . Rinsho Iyaku 6 (Suppl.5): 107-120, 1990 Marty M, on behalf of the Granise tron Study Gro up. A comparative study of the use of granisetro n, a selective 5-HT3 antagonist, versus a standard anti-emetic regimen of chlorprom azine plus dexamethasone in the treatment of cytostatic-induced emesis. Europea n Journ al of Cancer 26 (Suppl. I): 28-32, 1990 Milne RJ, Heel RC. Ondansetron. Th erapeutic use as an antiemetic. Drugs 41 (4): 574-595, 1991 Miner WD, Sanger GJ. Inh ibition of cisplatin-induced vomitin g by selective 5-hydroxytryptam ine Mvreceptor antagonism. British Jo urnal of Pharmacology 88: 497-499, 1986 Moertel CG, Reitemeier RJ. Controlled clinical studies of ora lly ad ministered antiemetic dr ugs. Gastroe nterology 57 (3): 262268, 1969 Monkovic I. New benzamide anti-emetics. Drugs of the Fut ure 14 (I): 41-49, 1989 Montgomery SA, Fineberg N. Is there a relationship between serotonin receptor subtypes and selectivity of response in specific psychiatric illnesses? British Jo urnal of Psychiat ry ISS (Suppl. 8): 63-70, 1989 Moss HE, Sanger GJ. Th e effects ofgranisetron, ICS 205-930 and onda nsetro n on the visceral pain reflex ind uced by duodenal distension. British Journal of Pharmacology 100: 497-501, 1990 Nelson DR, Thomas DR. [3H)-BRL 43694 (granisetron), a specific ligand for 5-HT3 binding sites in rat brain cortical membranes. Biochemical Pharmacology 38: 1693-I695, 1989 Niitani H, Hasegawa K, Kuriyama T, Nagao K, Yamaguchi T. Clinical evaluat ion of granisetron against nausea and vomiting ind uced by anticancer drugs. III. Comparative crossover stud y with met hylprednisolone. Rinsho Iyaku 6 (Suppl. 5): 87-105, 1990 Peroutka SJ. 5-Hydroxytrypta mine receptor subtypes. Annual Review of Neuroscience II : 45-60, 1988 Pintens H. Granisetron (BRL 43694) in the treat ment of cytostatic drug-induced emesis. A summary . Cancer Trea tment Reviews 17: 307-3 10, 1990 Pratt G O, Bowery NG, Kilpatrick GJ, Leslie RA, Barnes NM, et al. Consensus meeting agrees distributi on of 5-HT3 receptors in mam malian hindb rain. Trends in Pharmacological Sciences I I: 135-137, 1990 Pratt GO, Bowery NG. The 5-HT3 receptor ligand [3H)BRL 43694, binds to presynapt ic sites in the nucleus tractus solitari us of the rat. Neuro pharmacology 28 (12): 1367-1376, 1989 Prent ice H, Gra nisetro n Satellite Symposium, U ICC Congress, Ham burg, Germa ny, August 17, 1990 Priestman TJ . Clinical studies with ondanse tron in the cont rol of radiation-induced emesis. European Journ al of Clinical Oncology 25 (Suppl. I): S29-S33, 1989 Pritchard J F, Bryson JC, Kernodle AE, Benedetti TL, Powell JR . Influence of age and gender on the phar macoki netics of ondansetron, a 5-HT3 antagonist. Abstract PH-52. Clinical Pharmacology and Thera peutics 47: 161, 1990

Drugs 42 (5) 1991

Reynolds DJM , Leslie RA, Gra hame-Smit h DG, Harvey JM . Localizatio n of 5-HT 3 receptor binding sites in huma n dorsal vagal complex. European Journ al of Pharmacology 174: 127-130, 1989 Roila F, To nato M, Cognetti F, Cortesi E, Favalli G, et al. Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing onda nsetro n and ondansetro n plus dexa methasone. Journal of Clinical Oncology 9 (4): 675-678, 1991 Salzman C. A primer on geriatric psychopharmacology. American Journal of Psychiatry 139: 67-73, 1982 Sa nge r GJ , Nelso n D R. Selective and functio nal 5hydroxytryptam inej receptor antagonism by BRL 43694 (granisetron). European Jo urnal of Pharmacology 159: 113-124, 1989 Smith IE, on behalf of the Granisetron Study Gro up. A compa rison of two dose levels of granisetron in patients receiving moderately cytostatic chemotherapy. Europea n Journ al of Cancer 26 (Supp. I): 19-23, 1990 Smith RN. Safety of onda nsetro n. European Jo urnal of Cancer and Clinical Oncology 25 (Suppl. I): S47-S50, 1989 Smith WL, Callaham EM, Alphin RS. The eme tic activity of centrally administered cisplati n in cats and its antagonism by zacopride. Journ al of Pharmacy and Pharm acology 40: 142-143, 1988 Soukop M, on behalf of the Granisetron Study Gro up. A comparison of two dose levels of granisetro n in patien ts receiving high-dose cisplatin. Euro pean Jou rnal of Cancer 26 (Suppl. I): 15-19, 1990 Sridhar KS, Donnelly E. Com binatio n antiemetics for cisplatin chemothera py. Cancer 61: 1508-1517, 1988 Ta bona MV. An overview on the use of granisetron in the treatment of emesis associated with cytostat ic chemotherapy. European Journal of Cancer 26 (Suppl. I): S37-S4 I, 1990 Triozzi PL, Laszlo J. Optimum management of nausea and vom iting in cancer chemotherapy. Drugs 34: 136- I49, 1987 Upward JW, Arnold BDC, Link C, Pierce OM, Allen A, et al. The clinical pharmaco logy of granisetron (3 RL 43694), a novel specific 5-HT3 antagonist. Europea n Journal of Cancer 26 (Suppl. I): S12-S15, 1990 Venner P, for the Clinical Tria ls Group of the Natio nal Cancer Institute of Canada. Gra nisetron for high dose cisplatin (HDCP) ind uced emesis: a rando mized double-blind study. Abstract 1238. Proceedings of the American Society of Clinica l Oncology 9: 320, 1990 Warr D. A doub le-blind random ized comparison of the novel antie metic BRL 43694A versus dexamethasone plus prochlorperazine. Abstract P-0515. Proceedings of the European Congress of Clinical Oncology 5: 1989 Yoshida N, Mizumoto A, Iwanaga Y, !toh Z. Effects of 5-hydroxytryptam ine 3 receptor antagonists on gastroi ntestinal motor activity in conscious dogs. Journal of Pharmacology and Experimental Therapeutics 256 (I ): 272-278, 199 I Zussman BD, Clarkson A, Coates PE, Rapeport WG. Th e pharmacokinetic profile of BRL 43694, a novel c-H'Tj receptor antagonist, in healthy male volunteers. British Journal of Clinical Pharm acology 25 (I): 107P-108P, 1988

Correspondence: Greg L. Plosker, Adis International Limited, Private Bag, 41 Centorian Drive, Mairangi Bay, Auckland 10, New Zealand.