Pharmacological Management of
`Chemotherapy-Induced Nausea
`and Vomiting
`Focus on Recent Developments
`Rudolph M. Navari
`Department of Medicine, Indiana University School of Medicine, South Bend and Walther Cancer
`Research Center, University of Notre Dame, South Bend, Indiana, USA
`Contents
`Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
`1. Chemotherapy-Induced Nausea and Vomiting (CINV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
`1.1 Pathophysiology of Nausea and Vomiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
`1.2 Types of CINV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
`2. Antiemetic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
`2.1 Dopamine Receptor Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
`2.2 Serotonin 5-HT
`3 Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
`2.2.1 Palonosetron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
`2.3 Dopamine-Serotonin Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
`2.4 Neurokinin-1 Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
`2.4.1 Aprepitant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
`2.4.2 Fosaprepitant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
`2.4.3 Casopitant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
`2.5 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
`2.6 Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
`2.7 Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
`2.8 Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
`3. Clinical Management of CINV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
`3.1 Principles in the Management of CINV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
`3.2 Single-Day Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
`3.3 Multiple-Day Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
`3.4 Rescue Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
`3.5 Refractory Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
`4. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
`5. Future Developments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
`Abstract Chemotherapy-induced nausea and vomiting (CINV) is associated with a
`significant deterioration in quality of life. The emetogenicity of the chemo-
`therapeutic agents, repeated chemotherapy cycles and patient risk factors
`significantly influence CINV. Serotonin 5-HT
`3 receptor antagonists plus
`dexamethasone have significantly improved the control of acute CINV, but
`delayed CINV remains a significant clinical problem.
`REVIEW ARTICLE
`Drugs 2009; 69 (5): 515-533
`0012-6667/09/0005-0515/$55.55/0
`ª 2009 Adis Data Information BV. All rights reserved.
`HELSINN EXHIBIT 2036
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
`Page 1 of 19
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`Two new agents, palonosetron and aprepitant, have recently been ap-
`proved for the prevention of both acute and delayed CINV. Palonosetron is a
`second-generation 5-HT3 receptor antagonist with a longer half-life and a
`higher binding affinity than first-generation 5-HT3 receptor antagonists.
`Aprepitant is the first agent available in the new drug class of neurokinin-1
`(NK-1) receptor antagonists. Casopitant is another NK-1 receptor anta-
`gonist, which is under review by the US FDA after recent completion of
`phase III clinical trials.
`The introduction of these new agents has generated revised antiemetic
`guidelines for the prevention of CINV. Future studies may consider the use
`of palonosetron, aprepitant and casopitant with other antiemetic agents
`(e.g. olanzapine, gabapentin, cannabinoids) in moderately and highly emeto-
`genic chemotherapy, as well as in the clinical settings of multiple-day chemo-
`therapy and bone marrow transplantation.
`Chemotherapy-induced nausea and vomiting
`(CINV) is a distressing and common adverse event
`associated with cancer treatment. Seventy to eighty
`percent of patients undergoing chemotherapy
`experience emesis, with 10–44% experiencing anti-
`cipatory emesis.
`[1] CINV results in significant mor-
`bidity and negatively effects patient quality of life
`(QOL).
`[2,3] CINV may result in non-adherence to
`or dose reductions in chemotherapy.[4]
`Increased risk of CINV is associated with the
`type of chemotherapy administered (table I) and
`specific patient characteristics (table II).
`[5,6]
`CINV can result in weakness, weight loss, elec-
`trolyte imbalance, dehydration or anorexia, and
`is associated with a variety of complications, in-
`cluding fractures, oesophageal tears, decline in
`behavioural and mental status, and wound de-
`hiscence.
`[1] Patients who are dehydrated, debili-
`tated or malnourished, as well as those who have
`an electrolyte imbalance or those who have re-
`cently undergone surgery or radiation therapy,
`are at greater risk of experiencing serious com-
`plications from CINV.
`[1]
`Despite the introduction of more effective anti-
`emetic agents (serotonin 5-HT3 and neurokinin-1
`[NK-1] receptor antagonists), emesis and nausea
`remain a significant complication of chemotherapy.
`This article reviews the clinical agents available for
`the prevention and treatment of CINV. The use of
`these agents in various clinical settings is described
`using the recently established American Society
`of Clinical Oncology (ASCO) and the National
`Comprehensive Cancer Network (NCCN) guide-
`lines. The literature cited in this article consists of
`the primary clinical trials used for the US FDA
`approval of the various agents as well as recent
`comprehensive reviews.
`Table I. Emetic potential of chemotherapy agents[6]
`Emetogenic
`potential
`Definition Typical agents
`High Emesis in nearly
`all patients
`Cisplatin
`Dacarbazine
`Melphalan (high dose)
`Nitrogen mustard
`Moderate Emesis in >70 %
`of patients
`Anthracyclines
`Carboplatin
`Carmustine (high dose)
`Cyclophosphamide
`Ifosfamide
`Irinotecan
`Methotrexate (high dose)
`Oxaliplatin
`Topotecan
`Low Emesis in 10–70%
`of patients
`Etoposide
`Fluorouracil
`Gemcitabine
`Mitoxantrone
`Taxanes
`Vinblastine
`Vinorelbine
`Minimal Emesis in <10%
`of patients
`Bortezomib
`Hormones
`Vinca alkaloids
`Bleomycin
`516 Navari
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`1. Chemotherapy-Induced Nausea and
`Vomiting (CINV)
`1.1 Pathophysiology of Nausea and Vomiting
`The sensation of nausea and act of vomiting
`are protective reflexes that rid the intestine and
`stomach of toxic substances. The experience of
`nausea is subjective and nausea may be con-
`sidered a prodromal phase to the act of vomit-
`ing,
`[7] although significant nausea may occur
`without vomiting. Vomiting consists of a pre-
`ejection phase, retching and ejection, and is ac-
`companied by shivering and salivation. Vomiting
`is triggered when afferent impulses from the cere-
`bral cortex, chemoreceptor trigger zone (CTZ),
`pharynx and vagal afferent fibres of the gastro-
`intestinal (GI) tract travel to the vomiting centre
`(VC), located in the medulla (figure 1). Efferent
`impulses then travel from the VC to the abdom-
`inal muscles, salivation centre, cranial nerves and
`respiratory centre, causing vomiting. It is thought
`that chemotherapeutic agents cause vomiting
`by activating neurotransmitter receptors located
`in the CTZ, GI tract and VC. Serotonin, dopa-
`mine and substance P receptors are the pri-
`mary neuroreceptors involved in the emetic
`response.
`[1,7,8]
`The mechanisms of emesis are not well defined,
`but investigations suggest that it may be primarily
`mediated through neurotransmitters in the GI tract
`and the CNS. Figure 1 shows how chemotherapy
`agents, or their metabolites in the blood or cere-
`brospinal fluid, may directly affect areas in the
`medulla oblongata or may stimulate the GI tract
`via the vagus nerve to send impulses to the medulla.
`A VC, termed the ‘central pattern generator’ by
`some authors,
`[9] appears to be located in the lateral
`reticular formation of the medulla, which co-
`ordinates the mechanism of nausea and vomiting.
`An additional important area, also located in the
`medulla, is the CTZ in the area postrema near the
`fourth ventricle.
`[9] It is strongly suspected that the
`nucleus tractus solitarius (NTS) neurons lying
`ventrally to the area postrema initiate emesis.
`[10]
`This medullary area is a convergence point for
`projections arising from the area postrema, and the
`vestibular and vagal afferents.
`[10] The NTS is a
`good candidate for the site of action of centrally
`acting antiemetics.
`The main approach to the control of emesis
`has been to identify the active neurotransmit-
`ters and their receptors in the CNS and the
`GI tract that mediate the afferent inputs to the
`VC (figure 2). Agents that may block these
`Table II. Patient-related risk factors for emesis following
`chemotherapy[5,6]
`Major factors
`Female
`Age <50 y
`History of low prior chronic alcohol intake
`History of previous chemotherapy-induced emesis
`Minor factors
`History of motion sickness
`Emesis during past pregnancy
`Higher CNS centres
`Chemotherapy
`Cell damage
`Release of
`neuroactive agents
`Small
`intestine
`Activation of vagus
`and splanchnic nerves
`Medulla
`oblongata
`Increased afferent input
`to the CTZ and VC
`CTZ
`VC
`Fig. 1. Proposed pathways of chemotherapy-induced emesis.CTZ = chemoreceptor trigger zone;VC = vomiting centre.
`Management of Chemotherapy-Induced Nausea and Vomiting 517
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`neurotransmitter receptors in the CTZ, the
`VC or the GI tract may be useful in preventing or
`controlling emesis (table III).
`1.2 Types of CINV
`Five categories are used to classify CINV:
`acute, delayed, anticipatory, breakthrough and
`refractory. Nausea and vomiting may occur any
`time after the administration of chemotherapy,
`but the mechanisms appear different for CINV
`occurring in the first 24 hours after chemotherapy
`in contrast to that which occurs in the period of
`1–5 days after chemotherapy. In order to differ-
`entiate these mechanisms, the term acute-onset
`CINV refers to nausea and/or vomiting occurring
`within 24 hours of chemotherapy administra-
`tion.
`[5] The incidence of acute emesis reflects
`several treatment-related factors, including the
`environment in which chemotherapy is adminis-
`tered, the emetogenicity of the antiemetic ther-
`apy, the dosage of the emetogenic agents, and
`patient-related factors.
`[1,11]
`Nausea and/or vomiting that develop more than
`24 hours after chemotherapy administration is
`known as delayed emesis. Typically occurring with
`administration of carboplatin, doxorubicin or cy-
`clophosphamide, delayed emesis is more common
`in those who experience acute emesis. Other pre-
`d i c t i v ef a c t o r si n c l u d et h ed o s ea n dt h ee m t o g e n i -
`city of the chemotherapeutic agent, patient sex and
`age, and protection against nausea and vomiting in
`previous cycles of chemotherapy.
`[3,11] For cisplatin,
`which has been most extensively studied, delayed
`emesis reaches peak intensity 2–3 days subsequent
`to chemotherapy administration and can last up to
`aw e e k .
`[1,11,12]
`If patients experience CINV, they may develop a
`conditioned response known as anticipatory
`nausea and/or vomiting, which occurs before the
`administration of chemotherapy in future che-
`motherapy cycles and is attributed to the adverse
`memory of earlier CINV. Incidence rates for this
`type of nausea and vomiting range from 10% to
`45%, with nausea occurring more frequently.
`[1,13]
`Vomiting that occurs within 5 days after pro-
`phylactic use of antiemetic agents or requires
`‘rescue’ is called breakthrough emesis. Vomiting
`occurring after chemotherapy in subsequent
`chemotherapy cycles when antiemetic prophy-
`laxis and/or rescue have failed in earlier cycles is
`known as refractory emesis.
`[1]
`2. Antiemetic Agents
`2.1 Dopamine Receptor Antagonists
`Dopamine receptors are known to exist in the
`CTZ, and this is the main area of activity of the
`dopamine antagonists, such as the phenothiazines
`and the butyrophenones (droperidol, haloperidol).
`A high level of blockade of the dopamine receptors,
`however, results in extrapyramidal reactions, as
`well as disorientation and sedation, limiting the
`clinical use of these agents.
`2.2 Serotonin 5-HT3 Receptor Antagonists
`Serotonin receptors, specifically the 5-HT3 re-
`ceptors, exist in the CNS and in the GI tract. The
`5-HT
`3 receptor antagonists, such as dolasetron,
`granisetron, ondansetron and tropisetron, appear
`to act through both the CNS and the GI tract via
`the vagus and splanchnic nerves. The main toxi-
`cities of these 5-HT
`3 receptor antagonists consist
`only of a mild headache and occasional diarrhoea.
`The effectiveness of the 5-HT3 receptor anta-
`gonists in cisplatin-induced acute emesis[14-17] is
`believed to be due to a predominately peripheral
`site of action, the prevention of the stimulation
`of abdominal vagal afferent fibres by serotonin
`released from the enterochromaffin cells of the gut
`by cytotoxic agents. This has been well documented
`in animal ferret models.
`[18] 5-HT3 receptor anta-
`gonists have been less effective in delayed cisplatin-
`i n d u c e de m e s i sb o t hi nh u m a n s
`[19-24] a n di nf e r r e t
`GABA
`Histamine
`Endorphins
`Acetylcholine
`Dopamine
`Substance P
`Serotonin
`Emetic center
`Fig. 2. Neurotransmitters involved in emesis.
`518 Navari
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`models.[25] This may be due to the lack of central
`effect by the 5-HT3 receptor antagonists, as de-
`monstrated by the ineffectiveness of the 5-HT3 re-
`ceptor antagonists against the emesis induced by
`the centrally acting opioids (apomorphine, mor-
`phine) in experimental animals.
`[26]
`The introduction of 5-HT3 receptor antagonists
`for the prevention of CINV, as well as post-
`operative and radiotherapy-induced nausea and
`vomiting, has resulted in a major improvement in
`supportive care.
`[27-29] Treatment guidelines for the
`prevention of CINV recommended by a number of
`international groups
`[1,11-13] suggest the use of a
`5-HT3 receptor antagonist and dexamethasone pre-
`chemotherapy for the prevention of acute CINV,
`and the use of dexamethasone with or without a
`5-HT
`3 receptor antagonist following chemother-
`apy for the prevention of delayed nausea and
`vomiting.
`Table IV shows the 5-HT
`3 receptor anta-
`gonists currently in use. The first-generation
`5-HT
`3 receptor antagonists dolasetron, granise-
`tron, ondansetron, tropisetron,[30] azasetron[31]
`and ramosetron[32] are equivalent in efficacy and
`toxicities when used in the recommended doses
`and compete only on a cost basis.
`[33] They have
`not been associated with major toxicities, with
`the most commonly reported adverse events
`being mild headache, constipation and occasion-
`ally mild diarrhoea.
`[14,15,28,34,35] A prolongation
`of cardiac conduction intervals has been reported
`for this class of compounds with dolasetron being
`more extensively studied than granisetron and
`ondansetron, but there have been no reported
`clinical cardiovascular adverse events.
`[35]
`The first-generation 5-HT 3 receptor anta-
`gonists have not been as effective against delayed
`emesis as they are against acute CINV.[19-24] The
`available studies show that corticosteroids, alone
`or combined with either metoclopramide or a
`5-HT
`3 receptor antagonist in patients receiving
`cisplatin, reduce the incidence of delayed eme-
`sis, but it remains a significant problem.
`[29,36]
`The first-generation 5-HT3 receptor antagonists
`do not add significant efficacy to that obtained
`by dexamethasone alone in the control of delayed
`emesis.
`[22] Hickok et al. [24] reported that the
`first-generation 5-HT3 receptor antagonists used
`in the delayed period were no more effective
`than perchlorperazine in controlling nausea.
`A recent meta analysis[23] showed that there was
`neither clinical evidence nor considerations
`of cost effectiveness to justify using the first-
`generation 5-HT
`3 antagonists beyond 24 hours
`after chemotherapy for the prevention of delayed
`emesis.
`The second-generation 5-HT
`3 receptor anta-
`gonist palonosetron has been approved for
`clinical use, and studies suggest that it may
`Table IV. Serotonin 5-HT3 receptor antagonists and dosage before
`chemotherapya
`Antiemetic Route Dosage
`Azasetron IV 10 mg
`Dolasetron IV
`PO
`100 mg or 1.8 mg/kg
`100 mg
`Granisetron IV
`PO
`10 mg/kg or 1 mg
`2 mg (or 1 mg twice daily)
`Ondansetron IV
`PO
`8 mg or 0.15 mg/kg
`24 mg
`Ramosetron IV 0.30 mg
`Tropisetron IV or PO 5 mg
`Palonosetron IV 0.25 mg
`a The same doses are used for highly and moderately emetic
`chemotherapy.
`IV = intravenous; PO = oral.
`Table III. Antiemetic receptor antagonists
`Dopamine receptor
`antagonists
`Serotonin 5-HT
`3 receptor
`antagonists
`Dopamine/5-HT3 receptor
`antagonists
`Neurokinin-1 receptor
`antagonists
`Phenothiazines
`Butyrophenones
`Azasetron
`Dolasetron
`Granisetron
`Ondansetron
`Ramosetron
`Tropisetron
`Palonosetron
`Metoclopramide Aprepitant
`Fosaprepitant
`Casopitant
`Vofopitant
`CP-122 721
`CJ-11 794
`Management of Chemotherapy-Induced Nausea and Vomiting 519
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`have some efficacy in controlling delayed CINV
`compared with the first-generation 5-HT 3 re-
`ceptor antagonists.
`2.2.1 Palonosetron
`Palonosetron is a 5-HT3 receptor antagonist
`that has antiemetic activity at both central and
`GI sites. Compared with the older 5-HT
`3 recep-
`tor antagonists, it has a higher binding affinity to
`the 5-HT
`3 receptors, a higher potency, a signifi-
`cantly longer half-life (approximately 40 hours,
`four to five times longer than that of dolasetron,
`granisetron or ondansetron) and an excellent
`safety profile.
`[29] In two large studies[37,38] in pa-
`tients receiving moderately emetogenic chemo-
`therapy, complete response (no emesis, no rescue)
`was improved in the acute and the delayed period
`for the patients who received palonosetron
`0.25 mg alone compared with either ondansetron
`alone (570 patients; acute: 81.0 % vs 68.6 %,
`p = 0.008; delayed: 74.1% vs 55.1%,p < 0.001)
`[38]
`or dolasetron alone (592 patients; acute: 63.0%
`vs 52.9%,p = 0.049; delayed: 54.0% vs 38.7%,
`p = 0.004).
`[37] Dexamethasone was given with the
`5-HT3 receptor antagonists to only a small num-
`ber of patients (5%) in only one of these stu-
`dies,[37] and it remains to be determined if the
`differences in complete response would persist if
`dexamethasone was used.
`In another study, 650 patients receiving highly
`emetogenic chemotherapy (cisplatin‡60 mg/m
`2)
`received dexamethasone plus one of two doses of
`palonosetron (0.25 or 0.75 mg) or dexamethasone
`plus ondansetron (32 mg) pre-chemotherapy.
`Patients pre-treated with palonosetron (0.25 mg)
`plus dexamethasone had significantly higher
`complete response rates than those receiving
`ondansetron plus dexamethasone during the
`delayed and overall periods.
`[39]
`In an analysis of the patients in these studies
`who received repeated cycles of chemotherapy,
`Cartmell et al.
`[40] reported that the complete re-
`sponse rates for both acute and delayed CINV
`were maintained with the single intravenous dose
`of palonosetron without concomitant corticos-
`teroids.
`On the basis of the above studies, palonose-
`tron was approved by the FDA in July 2003, for
`the prevention of acute nausea and vomiting
`associated with initial and repeat courses of
`moderately and highly emetogenic cancer chemo-
`therapy; and for the prevention of delayed nau-
`sea and vomiting associated with initial and
`repeat courses of moderately emetogenic cancer
`chemotherapy.
`Despite the use of both first- and second-
`generation 5-HT
`3 receptor antagonists, the control
`of acute CINV, and especially delayed nausea and
`vomiting, is suboptimal with the agents listed in
`table IV. There is considerable opportunity for
`improvement with eitherthe addition or substitu-
`tion of new agents in current regimens.
`[29,36,41]
`2.3 Dopamine-Serotonin Receptor
`Antagonists
`Metoclopramide has antiemetic properties
`both in low doses as a dopamine antagonist and
`in high doses as a serotonin antagonist. The use
`of oral metoclopramide may be somewhat effi-
`cacious in relatively high doses (20 mg three times
`per day) in the delayed period, but may result in
`sedation and extrapyramidal side effects.
`[27,29,41]
`2.4 Neurokinin-1 Receptor Antagonists
`Substance P is a mammalian tachykinin that is
`found in vagal afferent neurons innervating the
`brainstem NTS, which sends impulses to the
`VC.
`[42] Substance P induces vomiting and binds
`to NK-1 receptors in the abdominal vagus, the
`NTS and the area postrema. [42] Compounds
`that block NK-1 receptors lessen emesis after
`cisplatin, ipecac, apomorphine and radiation
`therapy.
`[42] These observations have recently
`led to the development of NK-1 receptor an-
`tagonists and the study of the role they may
`play in controlling chemotherapy-induced nau-
`sea and emesis.
`Studies in rhesus monkeys using positron
`emission tomography scans have demonstrated
`that the experimental NK-1 receptor antagonist
`vofopitant, when administered peripherally, had
`a distribution into brain regions consistent with
`specific binding to NK-1 receptors.
`[43] Injection
`of the NK-1 receptor antagonists CP-99 994 or
`aprepitant directly into the vicinity of the NTS
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`neurons inhibited cisplatin-induced emesis in the
`ferret.[44] These results suggest that NK-1 re-
`ceptor antagonists may exert their main anti-
`emetic action by depressing the neural activity of
`the NTS neurons, with possibly some antiemetic
`effects from peripheral sites through a blockade
`of the NK-1 receptors located on the vagal
`terminals in the gut.
`[45-47]
`Tattersall et al.[47] have reported that aprepitant
`and its water-soluble phosphoryl prodrug, fosa-
`prepitant, inhibited acute and delayed cisplatin-
`induced emesis in a ferret animal model. A single
`dose of aprepitant prior to cisplatin decreased
`emesis during a 72-hour period and daily adminis-
`tration eliminated emesis during the entire 72-hour
`observation period. These animal studies provided
`the basis for the phase II and III clinical studies of
`NK-1 receptor antagonists.
`[48-60]
`2.4.1 Aprepitant
`The initial clinical studies using the NK-1
`receptor antagonists [48-50] demonstrated that
`the addition of a NK-1 receptor antagonist
`(CP-122 721, CJ-11 794, fosaprepitant, aprepi-
`tant) to a 5-HT
`3 receptor antagonist plus dexa-
`methasone prior to cisplatin chemotherapy
`improved the control of acute emesis compared
`with the 5-HT3 receptor antagonist plus dexa-
`methasone, and improved the control of delayed
`emesis compared with placebo. In addition, as a
`single agent, fosaprepitant had a similar effect on
`cisplatin-induced acute emesis as ondansetron,
`but was superior in the control of delayed eme-
`sis.
`[51] Subsequent studies[52,53] showed that the
`combination of aprepitant plus dexamethasone
`was similar to a 5-HT
`3 receptor antagonist plus
`dexamethasone in controlling acute emesis, was
`inferior in controlling acute emesis compared
`with triple therapy (aprepitant, 5-HT3 receptor
`antagonist, dexamethasone) and confirmed the
`improvement of delayed emesis with the use of
`aprepitant compared with placebo.
`In a dose administration study of oral aprepi-
`tant, which was the final capsule formulation,
`involving 563 chemotherapy-naive patients re-
`ceiving cisplatin (‡70 mg/m
`2), Chawla et al.[54]
`reported an improvement in the control of acute
`emesis when aprepitant was added to ondanse-
`tron plus dexamethasone and an improvement in
`the control of delayed emesis with the combina-
`tion of aprepitant and dexamethasone compared
`with dexamethasone alone. Aprepitant 125 mg
`on day 1 followed by 80 mg on subsequent days
`appeared to be the regimen appropriate for fur-
`ther study.
`In two randomized, double-blind, parallel,
`multicentre, controlled studies (520 patients in
`each study), patients received cisplatin (‡70 mg/m
`2)
`and were randomized to receive ‘standard ther-
`apy’ of a 5-HT
`3 receptor antagonist (ondanse-
`tron) plus dexamethasone pre-chemotherapy and
`dexamethasone post-chemotherapy (days 2–4) or
`‘standard therapy’ plus aprepitant given prior to
`chemotherapy and aprepitant plus dexametha-
`sone on days 2 and 3 post-chemotherapy.
`[55,56]
`The complete response (no emesis, no rescue) of
`the aprepitant group in both studies was signifi-
`cantly higher in the acute period (83–89%), the
`delayed period (68–75%) and overall (days 1–5)
`[62.7–72.7%] compared with that in the acute
`period (68–78%), the delayed period (47–56%)
`and overall (days 1–5) [43.3–52.3%] of the ‘stan-
`dard therapy’. The improvement in complete re-
`sponse with the addition of aprepitant was
`maintained over multiple cycles of chemother-
`apy.
`[57,61] Nausea was improved in the aprepitant
`group only in the delayed period in only one of
`the studies.
`[56]
`The studies discussed in this section formed
`the basis for the approval of aprepitant by the
`FDA in March 2003. In combination with other
`antiemetics, aprepitant is indicated for the pre-
`vention of acute and delayed nausea and vomit-
`ing associated with initial and repeat courses of
`highly emetogenic cancer chemotherapy, includ-
`ing high-dose cisplatin.
`[62,63]
`In a follow-up study to the two randomized
`studies described previously, the aprepitant regi-
`men was shown to have a higher complete response
`in patients receiving cisplatin not only to the 1-day
`ondansetron plus 4-day dexamethasone regimen in
`the previous trials, but also to a 4-day ondansetron
`plus 4-day dexamethasone regimen.
`[58]
`All of the initial studies using aprepitant were
`performed with cisplatin chemotherapy. Recently,
`Warr et al.
`[59] presented a study on the use of
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`aprepitant in 862 breast cancer patients re-
`ceiving moderately emetogenic chemotherapy. An
`aprepitant regimen of aprepitant 125 mg, on-
`dansetron 8 mg plus dexamethasone 12 mg pre-
`chemotherapy, then ondansetron (8 mg) 8 hours
`later on day 1, and aprepitant 80 mg/day on days
`2 and 3 was compared with a ‘standard’ regimen of
`ondansetron 8 mg plus dexamethasone 20 mg
`pre-chemotherapy, then ondansetron 8 mg 8 hours
`later on day 1, and ondansetron 8 mg twice daily
`on days 2 and 3. There was a significant improve-
`ment in complete response (no emesis, no rescue) in
`the 24 hours after chemotherapy in the patients
`receiving aprepitant, but there was no significant
`improvement in complete response on days 2–5i n
`the post-chemotherapy period when aprepitant
`alone was compared with ondansetron alone.
`The overall (days 1–5) complete response was sig-
`nificantly improved for the aprepitant-containing
`regimen, most likely as a result of the improvement
`in the first 24 hours. The control of nausea was not
`improved with the use of aprepitant.
`Aprepitant has been generally well tolerated
`with no reported serious adverse toxicities. Fati-
`gue, asthenia and hiccups have occurred in higher
`frequency in treatment groups compared with
`control groups.
`[55,56]
`2.4.2 Fosaprepitant
`A medical need exists for chemotherapy patients
`to have the option of parenteral administration of
`prophylactic antiemetics. Patients who cannot tol-
`erate orally administered medications because of
`active mucositis, difficulty in swallowing or poor
`function of the GI tract may require intravenous
`antiemetics prior to chemotherapy. Intravenous
`dexamethasone and intravenous 5-HT
`3 receptor
`antagonists are available, but only an oral form of
`aprepitant is available. An intravenous alternative
`to the current oral formulation for aprepitant
`would allow more convenient dose administration
`in some clinical settings while maintaining efficacy
`and overall therapeutic margins.
`The treatment of established CINV and the
`rescue of failed prophylaxis may be other poten-
`tial uses for an intravenous form of an antiemetic,
`although few studies have been conducted for
`these situations.
`Fosaprepitant is a water soluble phosphoryl
`prodrug for aprepitant, which, when adminis-
`tered intravenously, is converted to aprepitant
`within 30 minutes after administration via the
`action of ubiquitous phosphatases. The pharma-
`cological effect of fosaprepitant is attributed to
`aprepitant. As a result of the rapid conversion of
`fosaprepitant to the active form (aprepitant) by
`phosphatase enzymes, it is expected to provide
`the same aprepitant exposure in terms of area
`under the concentration-time curve (AUC) and a
`correspondingly similar antiemetic effect.
`[64]
`The tolerability of fosaprepitant has been
`evaluated in clinical trials with approximately
`150 patients.
`[51,53] In these studies, fosaprepitant
`was administered as a single intravenous dose of
`0.2–200 mg infused over 15–30 minutes, recon-
`stituted in saline or polysorbate 80 to concentra-
`tions ranging from 1 to 25 mg/mL.
`Fosaprepitant has also been administered in
`single daily doses of 25–100 mg on four con-
`secutive days. The studies showed acceptable
`venous tolerability at 1 mg /mL infused over
`15–30 minutes, but a concentration of 25 mg/mL
`at doses of 50 and 100 mg infused over 30 seconds,
`was associated with venous irritation. On the
`basis of these studies, it appears that the incidence
`of venous irritation depends on the total dose, the
`concentration and the rate of infusion.
`[65]
`During the development of aprepitant, certain
`studies that assessed the tolerability of fosaprepi-
`tant also evaluated its efficacy in patients receiving
`chemotherapy. In a comparison of fosaprepitant
`versus ondansetron, each given as monotherapy
`prior to cisplatin, fosaprepitant was active against
`cisplatin-induced emesis, particularly in the de-
`layed phase.
`[51] Moreover, an additional trial
`demonstrated the tolerability and efficacy of fosa-
`p r e p i t a n ta sp a r to fc o m b i n a t i o nt h e r a p yw i t h
`dexamethasone.
`[53] The clinical profile of fosapre-
`pitant in these early studies suggested that fosa-
`prepitant could be appropriate as an intravenous
`alternative to the aprepitant oral capsule.
`In a study in healthy volunteers, fosaprepitant
`was well tolerated up to 150 mg (1 mg/mL) and
`fosaprepitant 115 mg was AUC bioequivalent
`to aprepitant 125 mg.
`[65] Fosaprepitant in the
`intravenous dose of 115 mg has recently been
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`approved in the US (February 2008) and the EU
`(January 2008) as an alternative to oral aprepi-
`tant 125 mg on day 1 of a 3-day regimen, with
`oral aprepitant 80 mg administered on days 2
`and 3. Further studies are in progress to determine
`the efficacy, safety and tolerability of a single
`dose of intravenous fosaprepitant necessary to
`replace the 3-day oral regimen.
`[64]
`2.4.3 Casopitant
`Casopitant is a novel substituted piperazine
`derivative, which has potential for the treatment
`of