DRUG EVALUATION

Drugs 41 (4): 574-595, 1991 0012-6667/91/0004-0574/$11.00/0 © Adis International Limited. All rights reserved. ORE111

Ondansetron

Therapeutic Use as an Antiemetic Richard J. Milne and Rennie C. Heel Adis Drug Information Services, Auckland, New Zealand

Various sections of the manuscript reviewed by: P.R. Andrews, Department of Pharmacology, St Georges Medical School, London, England; N.M. Barnes, University of Bradford, Bradford, England; H.L. Borison, Dartmouth Medical School, Hanover, New Hampshire, USA; J. Bonneterre, Centre Oscar Lambret, Lille, France; B. Costall, University of Bradford, Bradford, England; T. Itoh, Tottori University School of Medicine, Japan; M.G. Kris, Solid Tumor Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA; J. Mansi, The Royal Marsden Hospital, England; R.I. Naylor, University of Bradford, Bradford, England; T.J. Priestman, Queen Elizabeth Hospital, Birmingham, England; S. Saito, The University of Tokushima, Tokushima, Japan; H.J. Schmoll, Medizinische Hochschule, Hannover, Federal Republic of Germany.

Contents 574

577 577 578 578 579 579

580 582 582 583 583 584

585 587 587 588

589 591

591

Summary I. Pharmacodynamic Properties 1.1 Activity at 5-HT3 Receptors, and Selectivity of Action 1.2 Effects on Ion Channels 1.3 Antiemetic Effects 1.3.1 Physiology and Pharmacology of Emesis 1.3.2 Antiemetic Action of Ondansetron and Other 5-HT3 Antagonists 1.3.3 Mechanisms of the Antiemetic Action of 5-HT3 Antagonists 2. Pharmacokinetic Properties 2.1 Absorption and Plasma Concentrations 2.2 Distribution and Elimination 3. Therapeutic Use 3.1 Chemotherapy-Induced Nausea and Vomiting 3.1.1 Noncomparative Studies 3.1.2 Comparisons with Placebo 3.1.3 Comparisons with Metoc1opramide 3.2 Radiation-Induced Nausea and Vomiting 4. Tolerability 5. Dosage and Administration 6. Place of Ondansetron in Antiemetic Therapy

Summary Synopsis Ondansetron (GR 38032F) is a highly selective 5-HTJ receptor antagonist, one of a new class of compounds which may have several therapeutic applications. Animal and clinical studies show that ondansetron redUces the 24-hour incidence and severity of nausea and vomiting induced by

Ondansetron in Emesis

575

cytotoxic drugs, including cisplatin, and by single exposure, high dose radiation. Ondansetron is more effective than high dose metoclopramide in the 24 hours following chemotherapy, and preliminary clinical evidence suggests that it is equally effective in the following 4 days. It is also more effective than the 'moderate' doses of metoclopramide used to suppress emesis following radiotherapy. The antiemetic efficacy of ondansetron is enhanced by dexamethasone in cisplatintreated patients. Importantly, extrapyramidal effects have not been reported with ondansetron. Further comparisons are required with standard combination antiemetic therapy to complement the data presently available. Thus, ondansetron is a promising new agent for prophylaxis against nausea and vomiting in chemotherapy and radiotherapy. It may be particularly useful in young and elderly patients who are more susceptible to extrapyramidal symptoms induced by high dose metoclopramide. With its improved tolerability and clinical response profiles, ondansetron represents an important advance in a difficult area of therapeutics.

Pharmacodynamic Properties Ondansetron is a new carbazole which blocks serotoninergic neurotransmission at serotonin3 (5-HT3) receptors. It is a potent, highly selective and competitive antagonist of the depolarising effects of serotonin in the rat and rabbit isolated vagus nerve and the rat superior cervical ganglion. Ondansetron blocks the depolarising effect of the 5-HT3-selective agonist 2-methyl-5-HT in longitudinal smooth muscle of guinea-pig ileum, and the Bezold-larisch reflex response to 2methyl-5-HT in anaesthetised rats and cats, but has little effect on 5-HT I and 5-HT 2 mediated responses or on ai, (31, muscarinic, nicotinic, histaminel, histamine2 or GABA a receptors. In vitro, it is at least 70 times more potent than metoclopramide at peripheral 5-HT3 receptors, but has no effect on stereotyped movements induced by dopamine agonists. In animal models parenterally administered ondansetron reduces the incidence of emetic episodes induced by radiation, cyclophosphamide and cisplatin-based chemotherapies. Since both radiation and cisplatin may release serotonin from chromaffin cells in the intestinal mucosa, and since serotonin activates vagal and possibly splanchnic afferent nerves which in turn reflexly induce nausea and vomiting, it has been proposed that ondansetron acts by blocking serotonininduced depolarisation of vagal afferent nerves. It may also block serotoninergic action in the chemoreceptor trigger zone in the area postrema and the nucleus tractus solitarius of the brainstem, which contain 5-HT3 binding sites probably located on vagal afferent nerve terminals. Ondansetron may slow colonic transit times but this effect is unrelated to its antiemetic action. It has no effect on motion sickness or on emesis induced by dopamine receptor agonists.

Pharmacokinetic Properties Ondansetron can be administered either intravenously or orally. Following oral administration of ondansetron 8mg, peak plasma concentrations of about 30 Itg/L are reached in I to 1.5 hours. Orally administered ondansetron is about 60% bioavailable in healthy subjects and about 75% bound to plasma proteins. The apparent volume of distribution is large (160L) and the mean elimination half-life is 3 hours. The clearance of ondansetron may be lower in the elderly. In healthy subjects 60% of a single intravenous radiolabelled dose is eliminated by the kidneys and 25% in faeces, mostly as metabolites. Clinically relevant metabolites have not been reported.

Therapeutic Use Most clinical trials have studied the control of vomiting over the first 24 hours following chemotherapy. Ondansetron has been given either intravenously (IV) or orally, as a loading dose within the first 30 minutes IV or I to 2 hours orally prior to chemotherapy, followed 'by continuous infusion or by 2 or 3 oral or intravenous doses at intervals of 2 to 8 hours. In a moderate size noncomparative study ondansetron (0.18 mg/kg intravenously 6- or 8hourly) completely controlled acute vomiting induced by cisplatin-based chemotherapy in 55% of patients, and reduced the number of emetic episodes to fewer than 3 in a further 20% of patients. Ondansetron delayed the onset of emesis from a median of 2.8 hours with placebo to

Drugs 41 (4) 1991

576

a median of 11.6 hours after administration of cisplatin, and reduced the incidence of emetic episodes 4-fold and the incidence of retching 3-fold during the 24 hours after administration. No cisplatin-treated patients receiving ondansetron required rescue antiemetic therapy compared with 12 of 14 receiving placebo. Compared with metoclopramide in several studies, including 4 double-blind crossover trials, ondansetron was more effective in ameliorating nausea and vomiting on the day of chemotherapy. In the largest trial complete or major control of emesis (fewer than 3 emetic episodes in 24 hours) was achieved in 75% of patients with ondansetron compared with 42% with metoclopramide. Preliminary evidence suggests that ondansetron is as efficacious as metoclopramide in the 4 days following cisplatin chemotherapy. In all patients included in one study, ondansetron Smg orally three times daily provided complete or major protection against vomiting induced by single high dose upper abdominal radiotherapy, and was more effective than metoclopramide IOmg orally three times daily.

Tolerability Overall, ondansetron is well tolerated by patients receiving radiotherapy or chemotherapy. The most frequently reported adverse event associated with ondansetron is headache, which responds to standard analgesics. However, it is noteworthy that in healthy subjects j)tadache occurred as frequently in placebo recipients as in those receiving ondansetron. MjId constipation or diarrhoea occurs in a small minority of patients. Importantly, extrapyramidal effects such as those produced by metoclopramide would not be expected from the pharmacodynamic profile of ondansetron and have not been reported in clinical trials or in studies with healthy volunteers.

Dosage and Administration When used to prevent nausea and vomiting induced by highly emetogenic chemotherapeutic regimens a loading dose of ondansetron Smg infused 30 minutes before cancer therapy, with 2 additional Smg doses administered at least 4 hours apart, or infusion of I mg/h for 24 hours, is recommended. For less emetogenic chemotherapeutic regimens, and for radiotherapy, ondansetron administered orally should be started as a loading dose (Smg) I to 2 hours prior to chemotherapy or radiotherapy and continued with 2 additional Smg doses at S-hour intervals. All regimens should be followed by Smg orally for up to 5 days.

Ondansetron (GR 38032F) is a carbazole (fig. 1) which exerts selective and potent antagonism of serotoninergic neurotransmission at serotoninJ (5HT J) receptors. In view of the distribution of 5-HTJ receptors in various regions of the mammalian brain, autonomic nerves and the enteric nervous system, and the known pharmacodynamic effects of 5-HTJ receptor antagonists, these agents have potential applications in the treatment of nausea and vomiting induced by cancer therapies, in visceral and chemically induced pain, and as anxiolytics and antipsychotics (reviewed in King & Sanger 1989). Cancer patients receiving cytotoxic therapies can experience severe nausea and vomiting, lasting for several days. They may also develop anticipatory

emesis and nausea. Repeated loss of gut contents may produce malaise, malnutrition, dehydration, and electrolyte imbalance, often necessitating continued hospitalisation and parenteral substitution. The patient may discontinue therapy, or refuse to accept more aggressive antitumour regimens (see Andrews et al. 1988). Until recently, metoclopramide was considered the best single agent available for prophylaxis against drug-induced emesis. However, it is effective only at doses which induce extrapyramidal symptoms in about 5% of patients (Kris et al. 1983; Smith 1989). The success of the highly emetogenic cytotoxic therapeutic agent cisplatin (cis-diamminedichloroplatinum; cisplatinum), which is used to treat certain solid tumours including those found in ovarian and testicular

577

Ondansetron in Emesis

Ondansetron

Metoclopramide

Serotonin

Fig. 1. Structures of serotonin, ondansetron (GR metoclopramide.

38032F) and

cancer, has highlighted the need for more effective means of controlling drug-induced nausea and vomiting. Following the demonstration that high dose metoclopramide blocks 5-HT3 receptors effectively (Fozard 1978; Miner & Sanger 1986), several selective 5-HT3 antagonists have been developed for clinical use as antiemetics. The first of these to reach the market is ondansetron. Clinical trials of ondansetron have been confined to its use as an antiemetic agent in cancer chemotherapy and radiation therapy, and this review focuses on this area, although a precis of its pharmacological properties is provided.

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

In the last few years 5-HT receptors have been classified into a diverse range of subtypes (reviewed by Peroutka 1988). The serotonin 'M receptor', first discovered in gut by Gaddum and Picarelli (1957), was recently reclassified as the 5-HT 3 receptor (Bradley et al. 1986; Peroutka 1988). Several selective antagonists of this receptor subtype

are now available. Ondansetron is a potent, highly selective competitive antagonist of the depolarising effects of serotonin in rat and rabbit isolated vagus nerve, rat superior cervical ganglion, and guineapig longitudinal smooth muscle (Butler et al. 1988; Ireland & Tyers 1987). The resolved R- and S-isomers were approximately equipotent as antagonists of serotonin on the rabbit vagus nerve (pKB values 8.61 ± 0.08 and 8.13 ± 0.08, respectively) [Butler et al. 1988]. Other studies (Butler et al. 1988) have provided evidence that ondansetron is selective for 5-HT3 receptors. Ondansetron (0.1 ~molfL) was a competitive antagonist of the depolarising effect of the 5-HT3-selective agonist 2-methyl-5-HT in the longitudinal muscle of the guinea-pig ileum. In contrast, it had little effect on 5-HT ,-like and 5HT2-mediated responses or on aq, f3" muscarinic, nicotinic, histamine" histamine2 or GABAa receptors in a variety of in vitro tissues, indicating its selectivity for the 5-HT3 receptor subtype. The selectivity ratio was at least lOOO-fold in all systems examined (Butler et al. 1988; Tyers et al. 1989). Ondansetron as well as several other potent 5-HT3 receptor antagonists have low affinities for central dopamine binding sites (Hamik & Peroutka 1989). Table I compares the potencies of ondansetron and metoclopramide at peripheral 5-HT3 receptors in vitro. As calculated from pA2 or pKB values, ondansetron was 69 to 126 times more potent than metoclopramide at peripheral 5-HT3 receptors. The rank order potency of ondansetron, metoclopramide and the experimental 5-HT3 antagonists ICS 205-930 and MOL 72222 at vagal nerve 5-HT3 receptors, which are probably involved in emesis induced by cytotoxic drugs (section 1.2), is ICS 205930 > ondansetron > MOL 72222 > metoclopramide (Butler et al. 1988). Ondansetron (EO SO 0.4 ~gjkg intravenously; 7.0 ~gjkg orally) antagonised the Bezold-larisch reflex response (transient bradycardia and hypotension) to the selective 5-HT3 agonist 2-methyl-5-HT in anaesthetised rats and cats, confirming that it blocks cardiac vagal 5-HT3 receptors, but had no effect on stereotyped movements induced by apomor-

578

Drugs 41 (4) 1991

Table I. Potencies of ondansetron and metoclopramide as antagonists of 5-HT or 2-methyl-5-HT in isolated tissue preparations (adapted from Butler et al. 1988)

Drug

Ondansetron Metoclopramide

Rabbit VN

Rat VN

Rat SCG

(p A2)

(pA2)

(pA2)

9.40 7.30

8.61 6.60

8.13 6.25

GPI (pKB)

7.31 5.47

Abbreviations: VN = vagus nerve; SCG = superior cervical ganglion; GPI = guinea-pig ileum; A2 = agonist concentration required to obtain 50% of maximum effect; pA2 = -loglO(A2); KB = antagonist concentration required to overcome the effects of doubling

the agonist concentration; pKB

= -IOgl0(KB).

phine and other dopamine agonists (Butler et al. 1988). Studies using radiolabelled 5-HT3 selective ligands such as GR65630 have identified 5-HT3 binding sites: on the vagus nerve (Kilpatrick et al. 1989) and the central terminals of the vagus nerve in the nucleus tractus solitarius of the rat (Pratt & Bowery 1989) and ferret (Leslie et al. 1990); in homogenates of rat entorhinal cortex, which is concerned with the sense of smell (Barnes et al. 1988a; Kilpatrick et al. 1987); in human amygdala and hippocampus, which are concerned with emotional expression and memory (Barnes et al. 1989; Kilpatrick et al. 1989); and in or adjacent to the area postrema of the rat, mouse, rabbit and ferret (Barnes et al. 1988b; Kilpatrick et al. 1989; Pratt et al. 1990), which is excited by emetogenic substances such as apomorphine and which relays information to the medullary vomiting centre (Borison & McCarthy 1983). Binding sites have also been identified in or close to the area postrema of these animal species, and in the same regions in human brains (Barnes et al. 1988a,b, 1989, 1990a; Pratt et al. 1990; Reynolds et al. 1989). Thus, ondansetron and other 5-HT3 antagonists bind to sites in many of the peripheral and central neural regions involved in emesis (section 1.3). 1.2 Effects on Ion Channels Serotonin has been found to induce disparate electrophysiological responses, such as activation of a potassium conductance leading to hyperpolarisation and neural inhibition, or suppression of po-

tassium conductance which enhances neural excitability (Colino & Halliwell 1987; Davies et al. 1987). In a hybrid neuroma-glioma cell line, serotonin bound to 5-HT3 receptors and thereby opened calcium channels, with subsequent calcium entry and depolarisation (Reiser & Hamprecht 1989). Cyclic GMP (guanosine monophosphate) levels were raised concomitantly, although the functional implication of this observation is not known (Reiser et al. 1989). 5-HT3-achvated inward (depolarising) currents were induced by serotonin in two other hybrid neuroma cell lines (Lambert et al. 1989) and rat hippocampal neurons in culture (Yakel et al. 1988). The identity of the permeant cation was not established, but it is likely to be sodium or calcium. Thus, it seems likely that ondansetron and other 5-HT3 antagonists block the serotonin-mediated increase in cationic conductance which mediates excitation of vagal primary afferent nerves and possibly also neurons in the chemoreceptor trigger zone. These findings strongly suggest that ondansetron acts at some of the sites which have been implicated in chemotherapy-induced emesis (section 1.3). 1.3 Antiemetic Effects Since the pione~ring work of Borison and Wang (1953) the physiology and pharmacology of nausea and emesis have been studied extensively in cats, dogs and more recently in ferrets (reviewed by Andrews& Hawthorn 1988).

Ondansetron in Emesis

1.3.1 Physiology and Pharmacology of Emesis The act of vomiting is performed by respiratory muscles which generate the abdominal and thoracic forces that expel gastric contents. It is usually associated with autonomic effects including gastrointestinal retroperistalsis, cold sweating, cutaneous vasoconstriction, tachycardia, and vagally induced changes in gut motility. However, since gastric contents can be expelled during autonomic blockade, the act of vomiting is clearly largely somatic rather than autonomic (reviewed by Borison & McCarthy 1983). Emesis is coordinated by a medullary 'vomiting centre' which receives somatic, visceral, cortical, and limbic neural inputs. Retching, which entails different intra-abdominal and thoracic pressure patterns and which does not result in expulsion of gastric contents, is probably coordinated by different but related pathways in the medulla (see Borison & McCarthy 1983 for details). The mechanisms underlying nausea are poorly understood, because it is difficult to extrapolate from animal behaviours and the neural mechanisms underlying conscious awareness are complex. Since nausea shares many of the features of vomiting, it may represent lower levels of activity in many of the same neural circuits, although as a mental rather than physical process it clearly involves other brain circuitry (see Andrews et al. 1988). Both nausea and vomiting can be induced by excessive activity in visceral afferent neurons in the abdominal vagus nerve and possibly the splanchnic nerves, or by inputs from a medullary chemoreceptor trigger zone in the area postrema of the medulla (Borison & McCarthy 1983). This region, accessible to the circulation and to cerebrospinal fluid, detects circulating emetogenic substances, including apomorphine (see Borison & McCarthy 1983). Local injection of the selective 5-HT 3 agonist 2-methyl-5-HT into regions adjacent to the area postrema of ferrets induced some ofthe prodroma of emesis (salivation, searching, licking, backwards walking, retching) [Higgins et al. 1989], suggesting that 5-HT3 receptors in or close to the area postrema would be activated by high levels of circu-

579

lating serotonin or by serotonin released locally from interneurons; however, direct evidence for these ideas is not yet available. Chemotherapy-induced nausea and vomiting respond to high doses of dopaminez receptor antagonists such as metoclopramide, which until recently were thought to reduce emesis by blocking dopaminez receptors in the chemoreceptor trigger zone (reviewed by Sanger & King 1988). However, metoclopramide is effective in only 40 to 60% of cancer patients receiving high doses of cisplatin (reviewed by Monkovic 1989). Because of its effects on dopaminergic neurotransmission, high dose metoclopramide can induce extrapyramidal symptoms (Indo & Ando 1982) and sedation, while prolonged use has been associated with tardive dyskinesia (Leopold 1984). Following the recognition that high doses of meto clop ramide block 5-HT3 receptors (Fozard 1978; Miner & Sanger 1986), selective 5-HT 3 antagonists were developed for antiemetic use. 1.3.2 Antiemetic Action of Ondansetron and Other 5-HT3 Antagonists Selective 5-HT3 antagonists, including ondansetron, have been tested for their antiemetic activity in ferrets because these animals are capable of a full behavioural expression of emesis and they have been used extensively as a model for cytotoxic drug-induced emesis. Ondansetron (0.01 or 0.1 mg/kg intravenously; 1 mg/kg intraperitoneally) [Higgins et al. 1989; Stables et al. 1987], ICS 205-930 (0.1 and 1.0 mg/kg intravenously) [Costall et al. 1986], GR65630A and MOL 72222 (0.1 and 1.0 mg/kg intraperitoneally, respectively) [Stables et al. 1987] reduced the frequency of emetic episodes caused by cisplatin administered immediately before or after the antiemetic drugs were · injected. Metoclopramide was 40 times less potent against cisplatin-induced emesis than the 5-HT3 antagonists (Stables et al. 1987). In addition, ondansetron (0.1 mg/kg subcutaneously) administered 40 minutes prior to high dosage whole body x-irradiation increased the latency to vomiting from 20 to 55 minutes. A higher dose (0.5 mg/kg) completely blocked the emesis induced by either x-ir-

580

radiation or cyclophosphamide, and reduced the frequency of retches induced by cyclophosphamide 25-fold (Stables et al. 1987). Thus, ondansetron and other 5-HT3 antagonists are more potent than metoclopramide in preventing or blocking emesis induced by chemotherapeutic agents, and probably radiation as well. Ondansetron is unlikely to block emesis induced by dopaminergic agents since it does not block dopamine receptors (section 1.1) and the 5HT3 antagonist BRL 24924 was ineffective against apomorphine-induced vomiting in ferrets (Miner et al. 1987). Antiemetic agents have traditionally been combined when one agent alone cannot control emesis. In ferrets, dexamethasone (2 mg/kg) administered with a suboptimal dose of ondansetron (0.1 mg/ kg) further prolonged the latency to retching or vomiting induced by cyclophosphamide and attenuated behaviours suggestive of nausea (Hawthorn & Cunningham 1990). Clinically, dexamethasone appears to enhance the antiemetic effect of ondansetron in cisplatin-treated patients (section 3.1.1). It is more difficult to study nausea in animal models. Cisplatin produces a number of behavioural changes which precede vomiting in the ferret. Following treatment with ondansetron, ferrets administered emetogenic doses of cisplatin displayed less searching behaviour, licking of lips, yawning and retrograde locomotion, suggesting that nausea had been reduced (Higgins et al. 1989). 1.3.3 Mechanisms of the Antiemetic Action of 5-HT3 Antagonists It has been proposed that both cytotoxic drugs and radiation cause cellular damage, thereby releasing a number of chemical mediators including serotonin from the intestinal mucosa (see Andrews et al. 1988). This serotonin is thought to depolarise vagal afferent nerves in the gut, or sensitise them to other stimuli such as the mechanical effects of pulsatile blood flow. Vagal afferent excitation in turn elicits the vomiting reflex (Hawthorn et al. 1988; Ireland & Tyers 1987). Several observations support this theory. Stables et al. (1987) have shown in the ferret that mucosal levels of serotonin and

Drugs 41 (4) 1991

5-HIAA increased 2-fold 27 hours after administration of an emetic dose of cisplatin. Importantly, urinary levels of 5-HIAA, the principal metabolite of serotonin (Cubeddu et al. 1990a), and plasma levels of serotonin (Barnes et al. 1990b) were dramatically enhanced following cisplatin infusion in some but not all cancer patients. The increase in serotonin levels appeared to correlate with emetic episodes (Cubeddu et al. 1990a). Figure 2 illustrates potential mechanisms underlying cytotoxic or radiation-induced emesis. It is not yet completely clear how ondansetron prevents or blocks emesis induced by cytotoxic drugs or radiation. In vitro, ondansetron antagonises the depolarising action of serotonin at 5-HT3 receptors on vagal afferent nerves (section 1.1). In anaesthetised ferrets, mechanoreceptive vagal afferent C fibres with receptive fields in the stomach or upper intestine were activated by intra-aortic serotonin. This effect was abolished by pretreatment with ondansetron (Andrews & Davidson 1990). Thus, ondansetron probably prevents or blocks cisplatin-induced emesis by antagonising the depolarising action of cisplatin-released 5-HT at 5HT 3 receptors on the terminals of vagal afferent nerves (reviewed by Andrews et al. 1988). Central vagal terminals contain 5-HT3 receptors (Leslie et al. 1990; Pratt & Bowery 1989) and may therefore also be involved, although this question requires more complete information about the functional role of serotonin at these sites. x-Irradiation, like chemotherapy, releases serotonin from gastrointestinal chromaffin cells (Matsuoka et al. 1962), and the vomiting and apparent nausea induced in cats by radiation can be blocked by vagotoiny plus dorsal column cordotomy (Borison et al. 1987). Thus, it seems reasonable to conclude that ondansetron and other 5-HT3 antagonists block the emetic effects of radiation and chemotherapeutic agents such as cisplatin largely by blocking input from visceral afferent nerves, including the vagus nerve. Ondansetron and other 5-HT 3 antagonists may also act directly at the chemoreceptor trigger zone to block the emetogenic effects of chemical mediators released by cytotoxic drugs. Ablation of the area postrema in cats (McCarthy & Borison 1984)

581

Ondansetron in Emesis

j I

Ondansetron

Vomiting

Area postrema

Higher 1----+==c=en=t;re""Ni~---1 CNS ... ~ NTS ~ areas PCRF ..,. ~ I ~ Visceral-somatic • motor nuclei

IV cytotoxic agents Abdominal vagus

Systemic circulation

I Emesis Ondansetron

~

~;::':15~tJ.. drUgS~

Portal

¥ __~~~n Got wall

Fig. 2. Proposed sites of the antiemetic action of ondansetron at 5-HT 3 receptors located peripherally on vagal afferent fibres in the gut wall and centrally in the area postrema, nucleus tractus solitarius (NTS) and other associated brain areas; M == other chemical mediators; peRF == parvicellular reticular formation (from Andrews et al. 1988; Pratt et al. 1990).

totally blocked cisplatin-induced emesis, although the cats were observed for only 6 hours so conclusions could not be drawn about the effects on delayed emesis. Regions in or adjacent to the area postrema of the rat, mouse, ferret and rabbit, which contains the chemoreceptor trigger zone, are particularly rich in 5-HT3 receptors (Kilpatrick et al. 1989; Pratt et al. 1990), and 5-HT 3 binding sites have also been reported in the vicinity of human area postrema (section 1.1). The most dense distribution of 5-HT3 receptors appears to be in the nucleus tractus solitarius, ventral to the area postrema, which receives vagal afferent nerves from the gut (see Pratt et al. 1990). Low doses of ondansetron (0.01 to O.IJ.tg) and other selective 5-HT3 antagonists injected directly into this region in ferrets inhibited emesis evoked by a preceding dose of cisplatin (Higgins et al. 1989). These results could not be explained by diffusion of the centrally injected compound into the general circulation, since the minimal effective dose of peripherally administered ondansetron was about lOOO-fold higher

(Higgins et al. 1989). The rank order of potency of 5-HT3 antagonists injected into the area postrema was similar to that of these compounds' affinities for 5-HT3 receptors in the rat vagus nerve (Kilpatrick et al. 1987). Taken together, these findings indicate that the antiemetic action of peripherally administered ondansetron is mediated by antagonism of the depolarising actions of 5-HT at 5-HT3 receptors in or adjacent to the chemoreceptor trigger zone as well as in the vagus nerve. It has been suggested that some antiemetics, including metoclopramide, may exert their effects partly by stimulating movement of the contents of the gut toward the anus, which may reduce afferent activity in the vagus nerve (Alphin et al. 1986). However, the prokinetic effects of ondansetron are equivocal, as shown in various animal and volunteer studies (Costall et al. 1987; Gidda et al. 1988; Gore et al. 1990; Talley et al. 1989, 1990). On balance, the evidence suggests that the effects of ondansetron on gut motility are unrelated to its antiemetic action.

582

Drugs 41 (4) 1991

100

A

::J

Oi 50

-=U c:

30

c:

20

4) c:

10

0 c..>

2

'"

500 mgf m2 + DOX or EPI > 40 mgf m2

Marty et al. (1990)

76

CIS 80-100 mgf m2 + others8

db, co

Schmoll (1989)

122

CYC + EPI (+ FLU)

mc, r, db, pa

IV for 8h

mc, r, db, pa

8mg IV

8mg PO 8-hourly

60mglV

20mg PO 8-hourly

85"

57

80"

62

mc, r,

8mglV

1 mgfh IV

3 mgfkg

0.5 mgfkgfh IV

58"

42

75"

42

20mg PO 8-hourly

69

62

72

61

IV 8mg PO

8mg PO 8-hourly

60mg IV

a Mild or no nausea. b Fewer than 3 emetic episodes per day. c CYC; EPI; FLU; METH; epidoxorubicin ; prednisolone; vindesinefbleomycin. d All patients naive to chemotherapy. e Cyclophosphamide; dacarbazine; doxor.ubicin; epirubicin. Abbreviations: mc '" multicentre; r '" randomised; db '" double-blind; co '" crossover; pa '" parallel; CIS '" cisplatin; CYC '" cyclophosphamide; DOX '" doxorubicin; EPI '" epirubicin ; FLU'" 5-fluorouracil; METH '" methotrexate; PO '" orally; IV '" intravenously; • '" statistically significant difference, p < 0.05.

tl

i:!

Cl;J

4>. .....

~

.....

'0

'0 .....

Ondansetron in Emesis

587

and dexamethasone offers promise in intractable chemotherapy-induced emesis. 3.1.2 Comparisons with Placebo Placebo-controlled trials of antiemetic agents are relatively uncommon in highly emetogenic chemotherapy, since 100% of the placebo group can experience emesis. Table IV summarises placebocontrolled studies of the antiemetic efficacy of ondansetron in cancer chemotherapy. In a doubleblind parallel study of cis platin (50 to 120 mg/m 2)treated patients, who received either ondansetron (0.15 mg/kg intravenous 3 times daily, 4-hourly; n = 14) or placebo (n = 14), the median time to the first episode of emesis for patients administered ondansetron was 11.6 hours compared with 2.8 hours for patients administered placebo. In the 24 hours after cisplatin the number of emetic episodes was 1.5 compared with 5.5, and the frequency of retches was 1.2 compared with 3.2 (Cubeddu et al. I 990a). The intense initial nausea and emesis which occurred within 2 to 8 hours after chemotherapy in placebo-treated patients was not evident in patients treated with ondansetron. Antiemetic 'rescue' treatment was not required by any ondansetron-treated patient, compared with 12 of 14 placebo recipients. Ondansetron (0.15 mg/kg intravenously or 8mg

orally, 3 times daily) gave complete or major control of emesis in 70 to 80% of patients receiving cisplatin- or cyclophosphamide-based chemotherapy, whereas emesis was controlled in 0 to 50% of patients receiving placebo (table IV). Nausea, assessed using a VAS, was scored highly by patients receiving placebo (median 64.3) but much lower by those receiving ondansetron (median 7.6) [Cubeddu et al. 1990a). Thus, ondansetron appears to be considerably more effective than placebo in controlling acute nausea and vomiting. 3.1.3 Comparisons with Metoclopramide Benzamides have been the mainstay of antiemetic therapy, but as single agents they have provided only partial relief for the more potent chemotherapy programmes. There is no completely effective single benzamide for all circumstances (Harrington et al. 1983; Kris et al. 1985; Triozzi & Laszlo 1987). One of the standard agents used in prophylaxis against nausea and vomiting induced by cisplatin is high dose metoclopramide, which unfortunately is associated with hypertensive crises, sedation, depression and extrapyramidal symptoms such as facial spasms, and which may be largely ineffective in 30 to 70% of patients (Kris et al. 1985; Monkovic 1989). Table V summarises the results of several mod-

Table IV. Studies comparing the acute antiemetic effects of ondansetron (ON) and placebo (PL) in cancer chemotherapy Reference

Number of evaluable patients

Chemotherapy

Study design

Ondansetron dose regimen

Efficacy

loading dose

complete + major control of emesis (% of patients)

maintenance dose

ON

PL

Cubeddu et al. (1990a)

ON 14 PL 14

CIS 50·120 mg/m 2

r, db, pa

0.15 mg/kg IV

0.15 mg/kg 8-hourly IV

78.5'

0

Cubeddu et al. (1990b)

ON 10 PL 10

CYC + DOX/ FLU/METH

r, db, pa

0.15 mg/kg IV

0.15 mg/kg 8-hourly IV

70'

20

Joss et al. (1990)

ON 39 PL 35

CYC + METH + FLU

r, db, pa

8mg PO

8mg PO 8-hourly

74'

50

=

=

=

=

= cyclophosphamide; DOX = doxorubicin;

Abbreviations: r randomised; db double-blincY,pa parallel; CIS cisplatin; CYC FLU 5-fluorouracil; METH methotrexate; , all differences statistically significant, p

=

=

=

< 0.05.

Drugs 41 (4) 1991

588

erate-size comparative studies of ondansetron and metoclopramide. Ondansetron was more effective overall than metoclopramide in controlling acute nausea (58 to 85% of patients vs 42 to 67%, respectively) and vomiting (72 to 86% of patients, vs 41 to 62%, respectively) in all but I trial, in which no statistical difference in therapeutic efficacy was established. Ondansetron has not yet been compared with nabilone, prochlorperazine, or other commonly used antiemetic agents or with combination antiemetic therapy. Marty et al. (1990) reported the results of a double-blind crossover study of 97 chemotherapynaive patients treated with cisplatin. Both antiemetic drugs were administered as a loading dose followed by 24-hour infusion. Of the 76 patients who completed the study, complete or nearly complete control of acute emesis was achieved in 75% of patients with ondansetron and in 42% with metoclopramide. Ondansetron was also more effective in controlling acute nausea as assessed by a VAS or a graded scale. There was a significant preference among patients for ondansetron. There was no significant difference between the 2 antiemetic treatments in the incidence or severity of vomiting which occurred in the 6 days following chemotherapy (delayed vomiting) [Marty et al. 1990]. Similar findings have been reported by de Mulder et al. (1990) [table V], although these authors found that nausea was controlled better with metoclopramide than with ondansetron in the 2 to 5 days following chemotherapy. Surprisingly, male patients responded better than female patients to both ondansetron (95% vs 65% complete or major response, for men and women, respectively) and metoclopramide (65% vs 31 %, respectively). Two other European studies including a total of 150 evaluable patients have shown ondansetron to be superior to metoclopramide in controlling acute emesis induced by several highly emetogenic combinations of chemotherapeutic agents other than cisplatin (Bonneterre et al. 1990; Kaasa et al. 1990). Treatment in both studies continued for at least 3 days. Complete antiemetic protection was achieved in 65% of 40 patients treated with ondansetron compared with 41 % of 42 patients treated with

l100 Q)

'"c 8. '"~

75,-

*

(; 50,E

-iij"

+ Q)

Qi

a

E

o

o

*

I-

t-

l-

I-

I-

25

o'-'--

n = 154 166 Day 1

143 152 2

135 139

3

54 4

52

33

32

5

Fig. 4. Comparative antiemetic efficacy of metoclopramide (20mg 8-hourly; D) and ondansetron (8mg 8-hourly; in 3 randomised double-blind studies; * significantly different from comparison drug (p < 0.05) [from Schmoll 1989).

metoclopramide, in the first 24 hours following chemotherapy with cyclophosphamide in combination with doxorubicin or epirubicin. Ondansetron was also more effective than metoclopramide on days 2 and 3 after chemotherapy (Kaasa et al. 1990). Of 68 breast cancer patients administered cyclophosphamide, fluorouracil and either doxorubicin or epirubicin, complete or major control of emesis was achieved in 86% of patients receiving ondansetron compared with 42% receiving metoclopramide on the day of chemotherapy. Ondansetron was also more effective in reducing acute nausea, and was more efficacious on days 2 and 3 of chemotherapy (Bonneterre et al. 1990). A meta-analysis (Schmoll 1989) of the combined data from 3 of the studies shown in table V showed that ondansetron was superior to metoclopramide in controlling emesis on days I, 2 and 4 (fig. 4). Almost two-thirds of the patients who received both drugs preferred ondansetron to metoclopramide. These results require confirmation in larger prospective studies. 3.2 Radiation-Induced Nausea and Vomiting Many patients receiving radiotherapy as part of their cancer treatment experience nausea and vomiting which, although less intense than that induced by cisplatin, may last throughout a course of 30 or

Ondansetron in Emesis

589

40 treatments. Currently available single agents control emesis in only 40 to 60% of such cases (Lucraft et al. 1982). Patients exposed to upper abdominal radiation are particularly susceptible. Priestman (1989) has reviewed data evaluating the efficacy of ondansetron in controlling radiation-induced emesis. In noncomparative pilot studies of patients receiving either high dose single exposure or fractionated radiotherapy, oral ondansetron controlled emesis in 59% of 22 patients administered 4mg 4 times daily and in 62% of 13 patients given 8mg 3 times daily (table VI). Nausea was controlled in lower proportions of patients. Ondansetron was compared with metoc1opramide in a randomised double-blind multicentre study inc1uding82 evaluable patients, 38 of whom received ondansetron (Priestman 1989; Priestman et al. 1990). Table VII shows the incidence and severity of vomiting in patients administered single exposure high dose (8 to lOGy) upper abdominal radiotherapy plus ondansetron (8mg orally) or metoclopramide (lOmg orally) given up to 2 hours before radiotherapy and thereafter at 8-hour intervals for 5 days. On the day of radiotherapy, when nausea and vomiting are usually at their most severe, complete or major control of vomiting was achieved in all 38 patients administered ondansetron compared with 31 of 44 patients (76%) ad-

ministered metoc1opramide. Efficacy rates for the 2 drugs were not statistically different on days 2 to 5. Control of nausea followed a similar pattern, with mild or no nausea being reported in 95% and 65% of patients receiving ondansetron and metoclopramide, respectively, on day I, and comparable efficacy on days 3 to 5. Thus, ondansetron appears to be more effective than usual doses of metoclopramide in controlling nausea and vomiting over the 24-hour period after single high dose upper abdominal radiotherapy. It is not clear whether any initial therapeutic advantage for ondansetron can be sustained beyond the 24 hours following radiotherapy. Studies comparing ondansetron with standard antiemetics such as prochlorperazine and chlorpromazine in fractionated courses of hem i- or whole body irradiation are in progress.

4. Tolerability The major problems encountered with high dose metoclopramide antiemetic therapy, which has been the mainstay of treatment, are dystonic reactions, which can be particularly troublesome in younger patients, and sedation, which is a feature of most antiemetics (Triozzi & Laszlo 1987). Extrapyramidal symptoms would not be expected from the

Table VI. Efficacy of ondansetron in preventing or ameliorating nausea and vomiting in patients given single exposure high dose radiotherapy8 (from Priestman 1989) Dose of ondansetron

Number of patients

Patients free of nausea or vomiting (%)

Severity (%) mild b

moderateC

severed

Vomiting 4mg qid 8mg tid

22 13

59 62

32 15

5 15

0 8

Nausea 4mg qid 8mg tid

22 12

36 50

36 17

14 8

14 25

a b c d

Midpoint doses 8-10Gy (single dose) or 2Gy(4-28 days); fields> 100cm2 . 1-2 vomiting episodes/day. 3-5 vomiting episodes/day. > 5 vomiting episodes/day. Abbreviations: qid = 4 times daily; tid = 3 times daily.

Drugs 41 (4) 1991

590

Table VII. Comparison of the efficacy of ondansetron (8mg tid orally for 5 days) and metoclopramide (10mg tid orally for 5 days) in controlling vomiting and retching following upper abdominal radiotherapy8 (from Priestman 1989) Number of patients

Day l' Ondansetron Metoclopramide

38

Worst day (day 2 or 3) Ondansetron Metoclopramide

38

a

44

43

Degree of control (%) complete

major

37 (97) 20 (45)

1 (3) 11 (25)

26 (68) 28 (65)

9 (24) 6 (14)

Dosage 8 to 10Gy; fields of 80 to 100cm2, dermatomes T10 to L2, or fields of 100 to 15Ocm2, dermatomes T8 to L3. Statistically significant difference between the 2 drugs in complete or major control of emesis; p < 0.001 .

Table VIII. Percentage of healthy subjects reporting adverse events following single or repeated dose administration of ondansetron orally or intravenously or placebo (from Blackwell & Harding 1989) Ondansetron

Placebo

single dose

repeat doses

single dose

repeat doses

Number of subjects

95

70

116

32

Headache

16.9

31.4

5.2

28.1

Lightheadedness/ dizziness/faintness

10.3

8.6

12.9

9.4

Abdominal discomfort

1.0

8.6

0

3.1

Constipation

0.5

7.1

0

0

pharmacodynamic profile of ondansetron, and have not been reported in clinical trials. Ondansetron is well tolerated overall. There is evidence in healthy subjects suggesting that ondansetron may differ from placebo only in gastrointestinal tolerability. Thus, in 223 volunteers receiving 1638 doses of ondansetron administered intravenously or orally and 516 doses of placebo the incidences of headache, and lightheadedness, dizziness or faintness were similar in both groups but ondansetron produced abdominal discomfort and constipation more frequently than placebo (table VIII; Blackwell & Harding 1989). Establishing a tolerability profile for an antiemetic used in chemotherapy is complicated by the baseline symptoms caused by the particular chemotherapeutic agents used. Adverse events

which have been attributed to ondansetron during therapeutic trials include headache, dry mouth, diarrhoea, constipation, lightheadedness, anxiety, sedation and blurred vision. After administration of either metoclopramide or ondansetron in moderate-size uncontrolled (n = 61) or controlled (n = 163) trials, the overall incidence of gastrointestinal tract symptoms and sedation was comparable for the two drugs (Smith 1989). In these studies, ondansetron appeared to be twice as likely to induce mild headache which responded to weak analgesics, whereas in contrast to metoclopramide it was not associated with the extrapyramidal symptoms which have led to withdrawal of 1 to 2% of patients receiving metoclopramide. Of 460 patients treated with ondansetron only 1 withdrew from therapy for reasons possibly associated with the drug, com-

Ondansetron in Emesis

pared with 7 of 404 patients treated with metoclopramide (Smith 1989). There have been 2 reported instances of anaphylactic reactions (Smith 1989), but no reported occurrences of cardiotoxicity to date, despite evidence from animal experiments that ondansetron blocks cardiac vagal 5-HT3 receptors (section 1.1). Laboratory screenings have revealed raised levels ofliver enzymes, including serum transaminase and serum AST levels in 2 to 6% of non-cisplatintreated patients and in up to 16% of cisplatin-treated patients (Smith 1989). Bilirubin levels were elevated by as much as 100% and amino transferase levels were elevated by as much as 200% in up to 16% of patients administered either metoclopramide or ondansetron. Such elevations in liver enzyme activity appear not to present a clinical problem, since in over 3000 patients treated with ondansetron there were no clinically significant hepatic sequelae (manufacturer's data, on file). Furthermore, Hesketh et al. (1990) have reported that in a study of 500 patients, elevations in ALT and AST levels were related to the cumulative dose of cisplatin administered, suggesting that changes in these enzymes may be caused by the chemotherapy rather than by ondansetron.

5. Dosage and Administration The optimal dosage of ondansetron is not yet known. The manufacturer's recommended dosage regimen for highly emetogenic chemotherapeutic regimens is a loading dose of ondansetron 8mg by 15-minute infusion or slow injection up to 30 minutes before chemotherapy, followed by infusion of 1 mg/h for 24 hours, or 2 additional doses administered at least 4 hours apart. For moderately emetogenic regimens including high dose radiotherapy, 8mg is administered orally 1 to 2 hours before chemotherapy, followed by two 8mg doses at 8hour intervals. An identical dosage regimen has been used in single exposure high dose radiotherapy. All regimens should be followed by 8mg orally 8-hourly for up to 5 days, to prevent delayed emesis. Some studies have divided the loading dose between intravenous and oral routes of adminis-

591

tration. Doses as low as 0.06 mg/kg intravenously appear to be effective in some patients in controlling cisplatin-induced nausea and vomiting, but the numbers of patients evaluated at each dose level were too low to allow firm conclusions (Grunberg et al. 1989; Kris et al. 1988). Orally administered ondansetron has been used successfully to control nausea and vomiting associated with both cisplatin-based (e.g. Grunberg et al. 1989; Hesketh et al. 1989; Marty et al. 1989) and other chemotherapies (e.g. Schmoll 1989).

6. Place of Ondansetron in Antiemetic Therapy Nausea and vomiting are distressing and potentially serious complications of cancer chemotherapy and radiotherapy which can lead to malnutrition, dehydration, electrolyte imbalance, prolonged hospitalisation, and in some instances withdrawal from potentially curative therapy. A milestone in antiemetic therapy was reached when Gralla et al. (1981) showed that high doses of the dopamine antagonist metoclopramide could reduce by 90% the median number of episodes of vomiting induced by cisplatin, one of the most emetogenic of chemotherapeutic agents. However, although metoclopramide is widely used as an antiemetic agent, it is effective only in 30 to 70% of patients and only at doses which have been associated with extrapyramidal side effects in about 5% of patients (Monkovic 1989). Following the recent demonstration that high dose metoclopramide blocks serotonin 5-HT3 receptors, and may therefore prevent emesis through serotoninergic mechanisms, several selective 5-HT3 antagonists have been developed for clinical use as antiemetics. The first of these to reach the market is ondansetron. In controlled clinical trials ondansetron gave complete or major control of vomiting in 72 to 86% of patients and nausea in 58 to 85% of patients over the first 24 hours following highly eI11etogenic chemotherapy. It was more effective than either placebo or metoclopramide. However, preliminary clinical evidence suggests that ondansetron is no more efficacious than metoclopramide in control-

Drugs 41 (4) 1991

592

ling emesis occurring on days 2 to 5 following cisplatin chemotherapy, although this requires confirmation. More extensive trials are also required to confirm whether ondansetron retains its efficacy with repeated use. Dexamethasone enhances the antiemetic efficacy of ondansetron. Preliminary clinical data suggest that ondansetron is also more effective than metoclopramide in preventing nausea and vomiting in the 24 hours following high dose single exposure upper abdominal radiotherapy. Ondansetron has not yet been compared with standard antiemetics such as prochlorperazine and chlorpromazine in fractionated courses of hem i- or whole body irradiation. Ondansetron is unlikely to be effective in motion sickness, but its pharmacodynamic profile suggests that it may have a place in prevention of nausea and vomiting induced by procedures which release serotonin from the gut, such as abdominal surgery, although clinical evidence supporting this supposition is not yet available. Ondansetron may prove to be particularly valuable in children and in elderly patients in whom the extrapyramidal symptoms of metoclopramide, which have not been reported with ondansetron, are particularly poorly tolerated, although the trials to date have not specifically reported findings with elderly patients. The increased efficacy of ondansetron compared with metoclopramide may relieve the requirement for supplementary benzodiazepines and antihistamines, and thus minimise the occurrence of heavy sedation. Further establishing the place of ondansetron as an antiemetic in chemotherapy will require controlled comparisons with standard cqmbination antiemetic therapy, using moderately emetogenic chemotherapeutic agents such as carboplatin, anthracyclines and alkylating agents. In summary, ondansetron is the first of a new class of drugs useful in preventing nausea and vomiting associated with cancer chemotherapy or radiotherapy. It is more efficacious than high dose metoclopramide in the 24 hours after chemotherapy, and may be particularly useful in patients who cannot tolerate the extrapyramidal side effects of metoclopramide or the sedation associated with

combinations of antiemetic agents. As might be expected at this stage of its development, some aspects of ondansetron's clinical profile need further study, but with its improved tolerability and superior efficacy to metoclopramide in highly emetogenic chemotherapy regimens, ondansetron represents an important advance in a difficult therapeutic area.

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Ondansetron in Emesis

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594

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2nd International Congress on Amino Acids and Analogues Date: 5-9 August 1991 Venue: Vienna, Austria For further information, please contact: Gert Lubec Department of Paediatrics University of Vienna Wiihringer GUrtel 18 A 1090 Vienna AUSTRIA