Aprepitant

Aprepitant
A Review of its Use in the Prevention of Nausea and Vomiting

Monique P. Curran and Dean M. Robinson
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

Various sections of the manuscript reviewed by:
P. De Negri, Department of Anesthesia, Intensive Care and Pain Medicine, IRCCS Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Potenza, Italy; P. Glare, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA; M. Markman, M.D. Anderson Cancer Center, University of Texas, Houston, Texas, USA; H.-J. Schmoll, Departments of Internal Medicine and Oncology/Hematology, Martin Luther University Halle/Wittenberg, Halle/Saale, Germany; S.J.P. Van Belle, Department of Medical Oncology, University Hospital Ghent, Ghent, Belgium.

Data Selection
Sources: Medical literature published in any language since 1980 on ‘aprepitant’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘aprepitant’ and (‘chemotherapy-induced nausea and vomiting’ or ‘CINV’) and (‘postoperative nausea and vomiting’ or ‘PONV’). Searches were last updated 27 July 2009.
Selection: Studies in patients at risk of developing chemotherapy-induced or postoperative nausea and vomiting who had received aprepitant. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Aprepitant, prevention of chemotherapy-induced nausea and vomiting, postoperative nausea and vomiting, pharmaco- dynamics, pharmacokinetics, therapeutic use, tolerability.

Contents
Summary 1854
1.Introduction 1856
2.Pharmacodynamic Properties 1856
3.Pharmacokinetic Properties 1857
3.1Absorption and Distribution 1857
3.2Metabolism and Elimination 1857
3.3Special Populations 1857
3.4Drug Interactions 1858
4.Therapeutic Efficacy 1858
4.1Chemotherapy-Induced Nausea and Vomiting (CINV) 1858
4.1.1Highly Emetogenic Chemotherapy 1860
4.1.2Moderately Emetogenic Chemotherapy 1863
4.1.3Special Populations 1865
4.2Postoperative Nausea and Vomiting (PONV) 1866
5.Pharmacoeconomic Considerations 1866
6.Tolerability 1868
6.1CINV 1868
6.1.1Highly Emetogenic Chemotherapy 1868

6.1.2Moderately Emetogenic Chemotherapy 1869
6.2PONV 1871
7.Dosage and Administration 1871
8.The Place of Aprepitant in the Prevention of Nausea and Vomiting 1872

Summary

Abstract
Aprepitant (Emendti ) is a neurokinin-1 (NK
1
) receptor antagonist that is able to

alleviate the emetic effects of substance P. When combined with a standard regi- men of a corticosteroid (dexamethasone) and a serotonin 5-HT3 receptor anta- gonist (ondansetron), oral aprepitant (125 mg on day 1 then 80 mg once daily on days 2 and 3) was effective in the prevention of acute and delayed chemotherapy- induced nausea and vomiting (CINV) associated with single or multiple cycles of highly emetogenic chemotherapy (HEC). This aprepitant regimen was also ef- fective in the prevention of CINV in patients treated with single or multiple cycles of moderately emetogenic chemotherapy (MEC). A single oral dose of aprepitant 40 mg administered prior to patients undergoing abdominal surgery was also ef- fective in the prevention of postoperative nausea and vomiting (PONV). Apre- pitant was generally well tolerated. Aprepitant is a recommended option for the treatment of PONV, and when combined with a corticosteroid and 5-HT3 re- ceptor antagonist is a recommended regimen for the treatment of CINV.

Pharmacological Properties
Aprepitant is a selective, high-affinity antagonist at human NK1 receptors and is consequently able to alleviate the emetic effects of substance P. Aprepitant has little or no affinity for serotonin 5-HT3, dopamine or corticosteroid receptors. Aprepitant crosses the blood-brain barrier. Aprepitant had no effect on gastro- intestinal motor function in healthy volunteers.
The pharmacokinetics of aprepitant are nonlinear across the recommended dose range, with clearance and absolute bioavailability decreasing with increasing dose. Following administration of a single oral dose of aprepitant 40 mg (re- commended dosage in the prevention of PONV) to healthy volunteers, the area under the plasma concentration-time curve (AUC) from time zero to infinity was 7.8 mg h/mL and the maximum plasma concentration (Cmax) was 0.7 mg/mL. The median time to Cmax (tmax) was »3.0 hours. Following administration of oral aprepitant 125 mg on day 1 followed by 80 mg once daily on days 2 and 3 (re- commended dosage in the prevention of CINV) to healthy volunteers, the AUC from 0 to 24 hours, the Cmax and tmax were 19.6 mg h/mL, 1.6 mg/mL and »4 hours, respectively, on day 1 and 21.2 mg h/mL, 1.4 mg/mL and »4 hours, respectively, on day 3. Aprepitant is excreted largely as metabolites in the urine and via biliary excretion in the faeces. The apparent terminal half-life was 9–13 hours.
Since aprepitant is metabolized by cytochrome P450 (CYP) 3A4, coadminis- tration of aprepitant and inhibitors or inducers of this isoenzyme will induce changes in the plasma levels of aprepitant. As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of coadministered substances that are metabolized through CYP3A4. As a moderate inducer of CYP2C9 and a mild inducer of CYP3A4, aprepitant can decrease plasma concentrations of substrates metabolized by these isoenzymes.

Therapeutic Efficacy In phase III studies in patients with solid tumours treated with a single cycle of HEC,
an aprepitant regimen (containing aprepitant 125 mg on day 1 then 80 mg once daily on days 2 and 3 plus dexamethasone and ondansetron) resulted in significantly higher complete response (no emesis and no rescue therapy) rates than with the

control regimen of ondansetron plus dexamethasone (63–73% vs 43–61%; p < 0.01) during the overall (day 1–5) phase after HEC administration. Complete response rates during the acute phase (day 1; 83–89% vs 68–79%) and the delayed phase (days 2–5; 68–75% vs 47–63%) were also significantly higher with the aprepitant than with the control regimen. In particular, the rate of no emesis was significantly higher with the aprepitant than the control regimen during the acute, delayed and overall phases. In a multiple-cycle extension study in which patients received of up to five additional cycles of HEC, the efficacy of the aprepitant regimen was maintained throughout each of the multiple cycles.
In patients with breast cancer treated with MEC (cyclophosphamide – anthracycline), an aprepitant regimen (aprepitant plus dexamethasone plus ondan- setron), compared with a control regimen (dexamethasone plus ondansetron) re- sulted in more patients achieving a complete response during the overall phase (51% vs 42%; p = 0.015), according to data from a large phase III trial. The between-group difference in complete response rates was primarily driven by the rate of no emesis (76% vs 59%; unadjusted p-value < 0.001), with no significant between-group dif- ference for the use of rescue medication. In a multiple-cycle extension of this trial, the advantage of the antiemetic effect of the aprepitant regimen over the control regimen seen in the first cycle was maintained throughout the additional three cycles of MEC. In a large phase III trial in patients with a variety of malignancies receiving MEC, significantly more recipients of a single cycle of an aprepitant than a control regimen had no emesis (76% vs 62%; p < 0.001) and a complete response (69% vs 56%; p < 0.001) during the overall phase.
An aprepitant regimen compared with a control regimen was considered to be cost-effective with regard to the cost per QALY in the prevention of CINV in two European studies, although not according to a US analysis.
Although a large phase III trial failed to prove that a single dose of oral aprepitant 40 mg was superior to ondansetron in preventing PONV (as measured by the pro- portion of patients with complete response in the 24 hours after surgery), a second phase III trial of similar design established that a single dose of aprepitant 40 mg was noninferior to ondansetron, with 64% versus 55% of patients achieving a complete response. Aprepitant was significantly more effective than ondansetron at prevent- ing vomiting in the 24 and 48 hours after surgery in both studies (p < 0.001).

Tolerability
An antiemetic regimen containing dexamethasone, ondansetron and aprepitant (administered administered orally as a single 125 mg dose on day 1 and then 80 mg once daily on days 2 and 3) was generally well tolerated when used in the pre- vention of CINV in cancer patients receiving single or multiple cycles of HEC or MEC. The incidence of adverse events in recipients of an aprepitant regimen was similar to that in recipients of the control regimen (dexamethasone plus ondan- setron). Commonly reported adverse events (‡10% of recipients) were asthenia/
fatigue, nausea, hiccups, constipation, diarrhoea and anorexia. Laboratory ad- verse events (‡3% of recipients) included proteinuria and increases in ALT, AST, blood urea nitrogen and serum creatinine. The adverse event profile of an apre- pitant regimen in patients receiving MEC was generally similar to that reported in patients receiving HEC.
The tolerability profile of a single oral dose of aprepitant 40 mg when used in the prevention of PONV was similar to that of a single intravenous dose of ondansetron in patients undergoing open, abdominal surgery who participated in two, large, well controlled studies. Most adverse events were mild to moderate in intensity. Com- monly reported adverse events (‡5% of recipients of either treatment group) were constipation, nausea, pruritus, pyrexia, hypotension, headache and flatulence.

1.Introduction

Nausea and vomiting are common adverse events experienced by patients following chemo- therapy or surgery.[1-4] Poorly controlled chemo- therapy-induced nausea and vomiting (CINV) or postoperative nausea and vomiting (PONV) can lead to dehydration, malnutrition and electrolyte imbalance, and may be associated with a variety of complications including oesophageal tears, declin- ing behavioural and mental status, and wound dehiscence. These symptoms can result in a re- duced willingness of the patient to be treated in the future or delays in discharge from hospital.
PONV can occur in as many as 79% of pa- tients,[3] while approximately 70–80% of all cancer patients receiving chemotherapy experience nausea and/or vomiting, with 10–40% of cancer patients experiencing anticipatory nausea and/or vomit- ing.[4] The incidence and severity of CINV are affected by a number of factors including the che- motherapy involved, the dosage of the chemo- therapy, the schedule and route of administration of the chemotherapy and patient-related factors such as age, sex and history of alcohol use.[4]
Nausea and/or vomiting induced by che- motherapy are commonly classified as acute, de- layed, anticipatory, breakthrough and refractory (table I).
Vomiting results from the stimulation of a

pulses then travel from the vomiting centre to the salivation centre, abdominal muscles, respiratory centre and cranial nerves causing vomiting.
Agents that have been used in the prevention of vomiting are those that block neurotransmitter receptors in the CNS and GI tract that mediate the afferent inputs, and include serotonin 5-HT3 receptor antagonists, corticosteroids, dopamine receptor antagonists and neurokinin-1 (NK1) re- ceptor antagonists. Since no single agent can be expected to provide complete protection against the various phases of emesis, a combination of antiemetic agents are usually administered.
Aprepitant (Emendti ) is a selective, high-affinity NK receptor antagonist that blocks the binding
1
of substance P.[5] This review examines the pharmacological properties, therapeutic efficacy, pharmacoeconomics and tolerability of orally ad- ministered aprepitant in the prevention of PONV in surgical patients, and in the prevention of CINV in cancer patients treated with highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC).

2.Pharmacodynamic Properties

The pharmacodynamic properties of aprepi- tant have been reviewed previously;[5] therefore, only a brief summary is provided herein.
Aprepitant selectively, and with high affinity,

multistep reflex pathway controlled in the
blocks the binding of substance P at NK1 re-

brain.[2] Vomiting is triggered when afferent im- pulses travel from the chemoreceptive trigger zone, the pharynx, the gastrointestinal (GI) tract and the cerebral cortex to the vomiting centre in the brain (located in the medulla). Efferent im-
ceptors in the CNS;[6] in vitro, the aprepitant concentration that displaced 50% of substance P from the NK1 receptors was 0.12 nmol/L.[7]
Aprepitant had low affinity for NK2 and NK3 receptors. It had little or no affinity for the se- rotonin 5-HT3, dopamine or corticosteroid re-

Table I. Types of chemotherapy-induced nausea and/or vomiting
ceptors (other neurotransmitters involved in the control of emesis).[6]

Acute

Delayed
Occurs within a few minutes to several hours after chemotherapy and usually resolves within 24 hours Occurs more than 24 hours after chemotherapy
In vivo and human positron emission tomo- graphy studies demonstrate that aprepitant

Anticipatory Occurs before a cycle of chemotherapy. A conditioned response
Breakthrough Occurs despite prophylactic treatment and/or requires rescue antiemetic agents
Refractory Occurs during subsequent treatment cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles
crosses the blood-brain barrier and occupies brain NK receptors.[7-9] A 125 mg dose of apre-
1
pitant resulted in ‡90% occupancy of NK1 re- ceptors in the CNS.[9]
Aprepitant displayed acute- and delayed- phase antiemetic effects in cisplatin-induced emesis in animal models[6,7,10,11] and augments

the antiemetic effect of the corticosteroid dexa- methasone or the 5-HT3 receptor antagonist on- dansetron in animal[11] and human studies (see section 4).
Aprepitant had no effect on GI motor func- tion in healthy volunteers.[12]

3.Pharmacokinetic Properties

Data in this section have largely been obtain- ed from the US[6] and European[13] prescribing information.

3.1Absorption and Distribution

Following administration of a single oral dose of aprepitant 40 mg (recommended dosage in the prevention of PONV; see section 7) in the fasted state, the area under the plasma concentration- time curve (AUC) from time zero to infinity was 7.8 mg h/mL and the maximum plasma con- centration (Cmax) was 0.7 mg/mL.[6] The median time to Cmax was »3.0 hours. Administration of a single dose of aprepitant 40 mg with a standard breakfast decreased the aprepitant Cmax by 18% but did not affect AUC.[13] The decrease in C
max
was not considered to be clinically relevant.
The pharmacokinetic profile of oral aprepi- tant administered as a single dose of 125 mg on day 1 followed by 80 mg once daily on days 2 and 3 (recommended dosage for the prevention of CINV; see section 7) to healthy volunteers is shown in table II.[6,13] The mean absolute oral bioavailability of aprepitant decreased with in- creasing dose; after doses of 80 and 125 mg under

fasting conditions was 67% and 59%.[13] Food had no clinically meaningful effect on the bio- availability of aprepitant.[6,13]
Total protein binding of aprepitant is >95% and the mean apparent volume of distribution at steady state is »70 L.[6] Aprepitant crosses the blood-brain barrier in humans and the placenta in animal studies.[6]

3.2Metabolism and Elimination

Aprepitant undergoes extensive metabo- lism.[6,13] Metabolism occurs largely as a result of oxidation at the morpholine ring and its side chain.[14] Seven weakly active metabolites have been identified. In vitro studies using human liver microsomes suggested that mainly cytochrome P450 (CYP) 3A4 and to a lesser extent CYP1A2 and CYP2C19 (but not CYP2D6, CYP2C9 or CYP2E1) were involved in the metabolism of aprepitant.[6,15] The unchanged drug accounted for »24% of the radioactivity in the plasma fol- lowing administration of a single oral dose of [14C]-aprepitant to healthy volunteers.[6]
Aprepitant is excreted largely as metabolites in the urine and via biliary excretion in the faeces.[6,13]
After a single 100 mg intravenous dose of a pro- drug of [14C]-aprepitant to healthy volunteers, 57% of the radioactivity was detected in the urine and 45% in the faeces. The apparent plasma clearance was dose dependent, decreasing with increasing dose and was »62–90 mL/min and the apparent terminal elimination half-life was »9–13 hours.[6]

3.3Special Populations
The pharmacokinetic profile of a 3-day regi-

Table II. Pharmacokinetic parameters of oral aprepitant when ad- ministered as a single 125 mg dose on day 1 followed by 80 mg once daily on days 2 and 3.[6,13] Twelve healthy volunteers were enrolled in the open-label study
men of aprepitant (125 mg on day 1 and then 80 mg/day on days 2 and 3) in 17 adolescent cancer patients[16] was similar to that in 12 heal-

Pharmacokinetic parameters
Day 1 Day 3
thy adult patients (data obtained from a previous study[17]). There are no clinically significant dif-

Mean Cmax (mg/mL) Mean AUC24 (mg h/mL)
Median tmax (h) Mean t (h)
½b
1.6
19.6 »4
1.4
21.2 »4 »9–13
ferences in the pharmacokinetics of aprepitant between male and female patients, between races (White, Black and Hispanic), between patients aged ‡65 years and those aged <65 years, and

AUC24 = area under the concentration-time curve from time 0 to 24 hours; Cmax = maximum plasma concentration; tmax = time to Cmax; t½b = elimination half-life.
between healthy volunteers and patients with mild to moderate hepatic insufficiency, those with severe renal insufficiency or those requiring

haemodialysis.[6,13,18] In these patients, no dosage adjustment is necessary. No data are available regarding the pharmacokinetics in patients with severe hepatic insufficiency.

3.4Drug Interactions

Aprepitant is a substrate and dose-dependent inhibitor of CYP3A4, and an inducer of CYP3A4, CYP2C9 and potentially other isoenzymes.[6,13,15]
Since aprepitant is metabolized by CYP3A4, coadministration of aprepitant and inhibitors or inducers of this isoenzyme will induce changes in the plasma levels of aprepitant (table III).[6,13]
Consequently, drugs such as ketoconazole, itra- conazole, nefazodone, troleandomycin, clari- thromycin, ritonavir and nelfinavir, which are strong inhibitors of CYP3A4, should be avoided as they may result in increased plasma con- centrations of aprepitant. Moderate inhibitors of CYP3A4 (e.g. diltiazem) should be administered with caution. Agents that strongly induce CYP3A4 activity (e.g. rifampicin [rifampin], car- bamazepine, phenytoin) may decrease the plasma level of aprepitant and should be avoided.[13]
As a moderate inhibitor of CYP3A4, a 3-day regimen of aprepitant (125 mg on day 1 and then 80 mg/day on days 2 and 3) may increase plasma concentrations of coadministered substances that are metabolized by CYP3A4 (table III). A single dose of aprepitant 40 mg is not expected to in- crease the plasma concentrations of agents that are metabolized by CYP3A4. Aprepitant should not be used concurrently with pimozide, terfena- dine, astemizole or cisapride.[6,13] Docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, im- atinib, vinorelbine and vincristine are agents that are metabolized by CYP3A4. However, there was no significant change in the pharmacokinetic parameters of docetaxel[23] or vinorelbine[24]
when these agents were coadministered with a 3-day aprepitant regimen (table III). Nevertheless, careful monitoring is advised when aprepitant is coadministered with any chemotherapeutic agent

aprepitant (table III). Therefore, it is recom- mended that the usual oral dexamethasone dosage should be reduced by approximately 50%, the usual intravenous methylprednisolone dosage should be reduced by approximately 25%, and the usual oral methylprednisolone dosage should be reduced by approximately 50% when coadministered with a 3-day regimen of aprepitant.[6,13]
Because aprepitant has been shown to induce CYP2C9, coadministration of aprepitant with agents that are known to be metabolized by CYP2C9, such as warfarin, tolbutamide and phenytoin, may result in lower plasma con- centrations of these agents (table III); therefore, caution is advised.[6,13]
Aprepitant reduced the plasma levels of coadministered oral hormonal contraceptives (table III); therefore, the efficacy of oral contra- ceptives may be reduced. Alternative or back-up methods of contraception are advised for 1 month following the last dose of aprepitant.[6,13]

4.Therapeutic Efficacy

This section focuses on the efficacy of aprepi- tant when used as part of an antiemetic regimen in the prevention of CINV in adult or adolescent cancer patients (section 4.1) and when used as monotherapy in the prevention of PONV in adult surgical patients (section 4.2). The endpoints used in these trials are shown in table IV.

4.1Chemotherapy-Induced Nausea and Vomiting (CINV)
The efficacy of aprepitant in the prevention of CINV has been evaluated in adult patients receiv- ing HEC (section 4.1.1) or MEC (section 4.1.2) and in adolescent patients receiving emetogenic chemo- therapy (section 4.1.3). Focus will be on phase III trials in which aprepitant was administered as part of an antiemetic regimen that also included a cor- ticosteroid (dexamethasone) and a serotonin

that is metabolized by CYP3A4. The cortico-
5-HT
3
receptor antagonist (ondansetron). Aprepi-

steroids dexamethasone and methylprednisolone are substrates of CYP3A4 and their plasma levels are increased when coadministered with
tant was administered orally as a single 125 mg dose on day 1 and then 80mg once daily on days 2 and 3. Specific details of the regimens and the

Table III. Drug interactions involving aprepitant. Agents were administered orally in healthy volunteers unless otherwise stated

Agent Dose of aprepitant (mg) [day(s) administered]
Antiemetics
Dosage of concomitant agent (mga ) [day(s) administered]
Clinically meaningful pharmacokinetics effects aprepitant concomitant agent

Dexamethasone
(CYP3A4 substrate)[6,13,19]
125 [1] then 80 [2–5] 20 [1] then 8 [2–5]
None
› AUC 2.2-fold (day 1 and 5)

Granisetron[20] 125 [1] then 80 [2, 3] 2 [1] None None

Methylprednisolone (CYP3A4 substrate)[6,13,19]
125 [1] then 80 [2, 3] 125 IV [1] then 40 [2, 3] None
› AUC 1.34-fold (day 1) and 2.5-fold (day 3)

Ondansetron (IV)[20] 375 [1] then 250 [2–5] 32 [1] None None
Palonosetron (IV)[21] 125 [1] then 80 [2, 3] 0.25 [1] None None
Chemotherapeutic agents
Cyclophosphamide[22] 125 [1] then 80 [2, 3] Recommended regimen None
Docetaxel[23] 125 [1] then 80 [2, 3] Recommended regimen None None
Vinorelbine[24] 125 [1] then 80 [2, 3] Recommended regimen None None
CYP3A4 inhibitors
Diltiazem[6,15] 230b [1–5] 360 [1–5] › AUC 2-fold › AUC 1.7-fold

Ketoconazole[6,13,15]
125 [1]
400 [1–10]
› AUC »5-fold › t½ 3-fold
None

CYP3A4 inducer

Rifampicin[6,13]
375 [9]
600 [1–14]
fl AUC 11-fold fl t½ 3-fold
None

CYP3A4 substrates
Midazolam[6,13] 125 [1] then 80 [2–5] 2 [1 and 5] None › AUC 2.3-fold (day 1) and 3.3-fold
(day 5)
Midazolam (IV)[6,13] 125 [1] then 80 [2,3] 2 [0, 4, 8, 15] None › AUC 25% (day 4) and fl 19%
(day 8)

Midazolam[6] 40 [1] 2 [1] None
CYP2C9 substrates
› AUC 1.2-fold (day 1)

Tolbutamide[6,13] 125 [1] then 80 [2, 3] 500 [0, 4, 8, 15] None fl AUC by 23%, 28% and 15% on
days 4, 8 and 15
Warfarin[6,13,17] 125 [1] then 80 [2, 3] Titrated to stable INR None fl Cmin of S-warfarin by 34% (day 8)
fl INR by 14% (day 5)
CYP2D6 substrate

Paroxetine[6,13]
85 or 170b
20 [1–14]
fl AUC »25% fl Cmax»20%
fl AUC »25% fl Cmax »20%

Other agents
Digoxin[25] 125 [7] then 80 [8–11] 0.25 [1–13] None None

Oral contraceptives[6,13]
100 [1–14] EE 35 mg [1–21]
NOR 1 [1–21]
None
fl AUC of EE by 43% fl AUC of NOR by 8%

125 [1] then 80 [2, 3] EE [1–21]
NOR [1–21]
fl AUC of EE by 19% (day 10)
fl Cmin of EE by £64% (days 9–21) fl Cmin of NOR by £60%

aUnless otherwise stated.
bAdministered in tablet form once daily; dosage comparable to capsule formulation stated.
AUC = area under the concentration-time curve; Cmax = maximum plasma concentration; Cmin = trough plasma concentrations; CYP = cytochrome P450; EE = ethinyl estradiol; INR = International Normalized Ratio; IV = intravenous; NOR = norethisterone (norethindrone); t½ = elimination half-life; fl indicates decreases; › indicates increases.

Table IV. Efficacy endpoints for randomized, double-blind, phase III trials involving aprepitant regimens used in the prevention of nausea and vomiting in patients receiving chemotherapy or post- operatively in patients who have undergone surgery

aprepitant (see section 3.4). Since the first emetic episodes occurred within the first 3 days of cispla- tin administration, and given the relatively long half-life of aprepitant (see section 3), aprepitant

Endpoint No emesis

No rescue therapy

No nausea
No significant nausea Complete response

Complete protection

The impact of CINV
Definition
No vomiting (oral expulsion of stomach contents), retching or dry heaves (an attempt to vomit that is not productive of stomach contents) regardless of use of rescue medication
No use of medication to treat established nausea or emesis Maximum nausea VAS rating <5 mm Maximum nausea VAS rating <25 mm No emesis (or no vomiting) and no rescue therapy
No emesis (or no vomiting), no rescue therapy, no significant nausea
FLIE[26] total score >108 out of a
was administered over 3 days in the subsequent phase III trials.
Three randomized, double-blind, multicentre, phase III trials assessed the efficacy of aprepitant in combination with dexamethasone and ondan- setron in the prevention of CINV in adult pa- tients treated with a single cycle of cisplatin-based HEC.[27-29] Two trials (one conducted primarily in the US and EU[27] and the other conducted only in Latin America[28]) were designed to be identical to allow the subsequent pooling and analysis of data.[35-38]
Patients (n = 530,[27] 569[28] and 489[29]) sched-

on daily life maximum possible score of 126
CINV = chemotherapy-induced nausea and vomiting; FLIE = Func- tional Living Index Emesis; VAS = visual analog scale from 0 (‘no nausea’) to 100 mm (‘worst possible nausea’).

dosage of each of the other antiemetic agents in- volved in the trials are presented in table V (HEC) and table VI (MEC).
The efficacy of an aprepitant-containing regi- men was assessed during the acute (0–24 hours), delayed (25–120 hours) and overall (0–120 hours) phases after the administration of HEC or MEC. The primary endpoint in these studies was gen- erally the overall complete response rate (table IV). The primary analysis generally involved the mod- ified intent-to-treat (mITT) population (patients who received chemotherapy, at least one dose of the study drug and had at least one post-treatment assessment during cycle 1).
uled to receive cisplatin ‡70mg/m2 were ran- domized to treatment with either an aprepitant regimen (aprepitant plus dexamethasone plus on- dansetron) or a control regimen (dexamethasone plus ondansetron; table V). In two of the trials,[27,28]
ondansetron was administered intravenously on day 1 only (table V). In the third phase III trial,[29]
ondansetron was administered intravenously on day 1 and then orally on days 2–4 (table V).
Patients (n = 851) who had completed a single cycle of HEC from the two identical phase III trials[27,28] continued in a multiple-cycle, double- blind, extension study in which patients were trea- ted with up to an additional five cycles of HEC.[36]
Additional antiemetic agents were not per- mitted within 2 days prior to cisplatin adminis-

Table V. Aprepitant (APR) or control (CON) regimens used in phase III trials in patients treated with highly emetogenic chemotherapy
Regimen Dose (mg) [day(s) administered]

4.1.1Highly Emetogenic Chemotherapy
Dose-ranging, phase II studies demonstrated the efficacy of aprepitant when added to a stan- dard antiemetic regimen (corticosteroid plus a 5-HT receptor antagonist) in the prevention of
3
CINV during single[33] or multiple[34] cycles of cisplatin-based HEC. The phase II trials supported
APR[27-29]

CON[27,28]

CON[29]
APR 125 [1] POa then 80 od [2, 3] PO DEX 12 [1] POb then 8 od [2–4] PO OND 32 [1] IV
DEX 20 [1] POb then 8 bid [2–4] PO OND 32 [1] IV
DEX 20 [1] POb then 8 bid [2–4] PO OND 32 [1] IV then 8 bid [2–4] PO

the use of the corticosteroid dexamethasone for the control of acute emesis and demonstrated the need to lower the dosage of dexamethasone in order to compensate for the inhibition of its metabolism by
aAdministered 1 h prior to chemotherapy.
bAdministered 30 min prior to chemotherapy.
bid = twice daily; DEX = dexamethasone; IV = intravenously; od = once daily; OND = ondansetron; PO = orally.

Table VI. Aprepitant (APR) or control (CON) regimens used in phase III trials in patients treated with moderately emetogenic chemotherapy. All agents were administered orally
Regimen Dose (mg) [day(s) administered]

significantly higher with the aprepitant than with the control regimen (see table VII for p-values).
A combined analysis[38] of the two identical phase III trials[27,28] indicated that the aprepitant

APR[30-32]

CON[30-32]
APR 125 [1]a then 80 od [2, 3]
DEX 12 [1]b OND 8 bid [1]
DEX 20 [1]b OND 8 bid [1–3]
regimen provided greater overall complete re- sponse than the control regimen irrespective of sex (women 66% vs 41%, p < 0.001; men 69% vs 53%, p < 0.001).

aAdministered 1 h prior to chemotherapy.
bAdministered 30 minutes prior to chemotherapy.
bid = twice daily; DEX = dexamethasone; od = once daily; OND = ondansetron.

tration (day 1) or between days 1–6 (except as rescue medication for established nausea or vo- miting). Additional HEC (Hesketh level ‡3) was permitted only on day 1 and was administered to 10–17% of patients.[27-29] Concomitant therapy administered in addition to cisplatin included etoposide, fluorouracil, gemcitabine, vinorelbine, paclitaxel, cyclophosphamide, doxorubicin and docetaxel.[6]
Patients included in the studies were cisplatin- naive, aged ‡18 years, with solid tumours confirmed by histology, a Karnofsky score ‡60 and a life ex- pectancy greater ‡3 months. Exclusion criteria included abnormal laboratory values (for plate- lets, absolute neutrophils, AST, ALT, bilirubin or creatinine), a planned multiple-day, cisplatin-based chemotherapy regimen in a single cycle, MEC or HEC in the 6 days prior to and/or after the day of cisplatin administration, radiation therapy to the abdomen or pelvis within 1 week before HEC ad- ministration or on days 1–6 after HEC.[27-29]

Single-Cycle Chemotherapy
Phase III studies in patients with solid tu- mours treated with a single cycle of HEC demon- strated that a regimen containing aprepitant plus dexamethasone plus ondansetron resulted in sig- nificantly more patients with an overall complete response (primary endpoint) than with the con- trol regimen of dexamethasone plus ondansetron alone (63–73% vs 43–61%; p < 0.01 for all com- parisons; table VII).[27-29] Complete response rates during the acute (83–89% vs 68–79%) and delayed (68–75% vs 47–63%) phases were also
Significantly more patients treated with the aprepitant than the control regimen had no em- esis during the acute, delayed and overall phases (table VII), according to data from all three trials.[27-29] Moreover, Kaplan-Meier analysis indicated that the time to the first emesis after the initiation of HEC was longer with the aprepitant regimen than the control regimen (p < 0.001; based on the log-rank test).[27-29] Combined data from the two identical studies indicated the dif- ference between the two groups on the Kaplan- Meier curves began at approximately 12–16 hours after HEC administration (statistical analyses not reported).[39] Similarly, in the third study,[29] the Kaplan-Meier curves for each of the treatment regimens began to visually separate at 10 hours, with the between-group difference being signi- ficant after 21 hours (p < 0.05; backwards log- rank procedure).
According to a combined analysis[35] of the two identical phase III trials,[27,28] delayed emesis was correlated with, but not entirely dependent upon, the presence of acute emesis. Across both studies, acute emesis occurred in 13% of recipients of the aprepi- tant regimen and 26% of recipients of the control regimen (p < 0.01). Of these patients, the incidence of subsequent delayed emesis was 17% lower with the aprepitant compared with the control regimen. Of the patients who did not experience acute emesis, the incidence of delayed emesis was 16% less with apre- pitant than with the control. Thus, it was concluded by the researchers that aprepitant conferred a similar degree of improvement in delayed phase protection, irrespective of acute emesis. They concluded that the decrease in delayed emesis could not be attributed to a ‘carry over’ effect that resulted from a decrease in acute emesis.
The effect of aprepitant on nausea was not as apparent as its effect on emesis. In one study,[28]
there was a significant difference between the

Table VII. Clinical efficacy of an oral aprepitant (APR) antiemetic regimen in patients (pts) receiving one cycle of highly emetogenic cisplatin- based chemotherapya in randomized, double-blind, multicentre, phase III trials.[27-29] Data have also been obtained from the aprepitant manufacturer’s US prescribing information[6] and the EU summary of product characteristics.[13] Pts were randomized to an APR (APR plus dexamethasone plus ondansetron) or a control (CON) regimen (dexamethasone plus ondansetron; see table V for further dosage and administration details). Placebo tablets/capsules were administered to maintain blinding. Endpoints were assessed during the acute (day 1), delayed (days 2–5) or overall (days 1–5) phases after chemotherapy. Analyses were performed on the modified intent-to-treat populationb
Study Regimen Phase Endpointc (% pts)

(pt no.)
complete response
complete protection
no emesis no nausea no significant
nausea
no rescue medication

Hesketh et al.[27] APR Acute 89*** 85** 90** 72d 91d 94*
(260)Delayed 75*** 66** 81** 51 75 81*
Overall 73***e 63** 78** 48 73 81**
CON Acute 78 75 79 69d 87d 89
(261)Delayed 56 52 59 48 69 74
Overall 52e 49 55 44 66 71
Poli-Bigelli et al.[28] APR Acute 83*** 80** 84** 96**
(261)f Delayed 68*** 61** 72** 53** 73 83*
Overall 63***e 56** 66** 49* 71 82**
CON Acute 68 65 69 90
(263) Delayed 47 44 48 40 65 74
Overall 43e 41e 44 39 64 73
Schmoll et al.[29] APR Acute 88** 89** 92 94
(243) Delayed 74** 79*** 76 84
Overall 72**e 77**e 73 82
CON Acute 79 81 90 93
(241) Delayed 63 64 72 82

Overall 61e 62e
aPts received a single dose of intravenous cisplatin ‡70 mg/m2 on day 1 of cycle 1.
70 80

bPts who received chemotherapy and at least one dose of the study drug and had at least one post-treatment assessment during cycle 1.
cSee table IV for definition of endpoints.
dStatistical analysis not performed.
ePrimary endpoint.
fThere were 261 pts in the acute phase and 260 pts in the delayed and overall phases. * p < 0.05, ** p < 0.01, *** p < 0.001 vs CON.

aprepitant and control regimen in the number of patients with no nausea in the delayed and overall phases (table VII). There was no between-group difference in the number of patients with no sig- nificant nausea in any of the three studies.[27-29]
The number of patients requiring rescue med- ication was significantly lower in recipients of the aprepitant regimen than the control regimen during all phases after chemotherapy in two[27,28]
of the three[27-29] trials (table VII).
Two studies assessed the impact of CINV on daily life, according to the total score on the Functional Living Index Emesis (FLIE) ques- tionnaire (see table IV for further explanation of
this endpoint).[27,28] Significantly more recipients of the aprepitant than the control regimen experi- enced minimal or no impact of CINV on daily living, according to data from the two individual studies (75% vs 64%[28] and 74% vs 64%;[27] statis- tical analyses not reported) or from a combined analysis of the two studies (74% vs 64%; p < 0.01; analysis not adjusted for multiplicity).[35]

Multiple-Cycle Chemotherapy
In patients who continued into the multiple- cycle extension study,[36] the efficacy of the apre- pitant regimen was maintained throughout each of the multiple HEC cycles (up to five additional

cycles; see figure 1). In every cycle, the estimated probability of no emesis and no significant nau- sea over the 5 days after HEC administration was significantly higher with the aprepitant than the control regimen (see figure 1).

4.1.2Moderately Emetogenic Chemotherapy
Randomized, double-blind, multicentre, phase III trials assessed the efficacy of aprepitant in combination with dexamethasone and ondanse- tron in the prevention of CINV in adult patients with breast cancer[30] or various malignancies[31]
who were treated with a single cycle of MEC. Patients (n = 866[30] and 848[31]) were random-
ized to treatment with an aprepitant (aprepitant plus dexamethasone plus ondansetron) regimen or a control (dexamethasone plus ondansetron) regi- men (see table VI for further details). In addition, patients (n = 744) who had completed one cycle of MEC from one of these trials[30] entered a double- blind, multiple-extension study during which they received up to three additional cycles of MEC.[40]
A smaller, double-blind, single-centre study also randomized 127 Chinese patients receiving MEC

to an aprepitant or control regimen (table VI).[32]
All agents were administered orally.
Eligible patients were aged ‡18 years of age, naive to MEC or HEC, had histologically con- firmed breast cancer[30,32] or any histologically or cytologically confirmed malignant disease[31] re- quiring treatment with non-cisplatin-based MEC, Karnofsky scores ‡60 and a predicted life expec- tancy of ‡4 months. Exclusion criteria included a symptomatic, CNS malignancy, vomiting in the 24 hours prior to treatment, abnormal laboratory values (platelets, absolute neutrophils, AST, ALT, bilirubin or creatinine), planned cisplatin- based chemotherapy, MEC or HEC in the week prior to treatment, radiation therapy to the ab- domen or pelvis within 1 week of treatment and up to 6 days after treatment, or systemic corti- costeroid use.
In the studies in patients with breast cancer,[30,32]
patients were scheduled for treatment with intra- venous cyclophosphamide 750–1500mg/m2 mono- therapy, or intravenous cyclophosphamide
500–1500mg/m2 plus intravenous doxorubicin £60mg/m2 or epirubicin £100mg/m2.

Aprepitant regimen

70

60

50

40

30

20

10

0
Control regimen

Cycle 1 (n = 1038)
Cycle 2 (n =589)
Cycle 3 (n = 448)
Cycle 4 (n = 312)
Cycle 5 (n = 212)
Cycle 6 (n = 167)

Fig. 1. Estimated probability of overall rate of cancer patients (pts) with no emesis and no significant nausea after treatment with an aprepitant (aprepitant plus dexamethasone plus ondansetron) or control (dexamethasone plus ondansetron) regimen in the 5 days after administration of highly emetogenic, cisplatin-based chemotherapy (HEC). Pooled data[36] from the multiple-cycle extensions of two randomized, double-blind, multicentre studies.[27,28] Pts received an aprepitant or control regimen (see table V for details of dosage) for up to an additional five cycles of HEC. Analyses are based on the modified intent-to-treat population and used a transitional probabilities approach. * p < 0.01, ** p < 0.001 vs control.

Table VIII. Clinical efficacy of oral aprepitant (APR) in the prevention of chemotherapy-induced nausea and vomiting in patients (pts) with breast cancer[30] or various malignancies[31] receiving moderately emetogenic chemotherapy. Data were obtained from the modified intent-to- treat populationa of randomized, double-blind, multicentre,[30,31] phase III trials. Data have also been obtained from the US prescribing information[6] and the EU summary of product characteristics.[13] Pts were randomised to an APR regimen (APR plus dexamethasone plus ondansetron) or a control (CON) regimen (dexamethasone plus ondansetron; see table VI for further details of dosage and days of adminis- tration). All antiemetic agents were administered orally. Placebo tablets/capsules were administered to maintain blinding. Efficacy endpoints were assessed in cycle 1 during the acute (day 1), delayed (days 2–5) or overall (days 1–5) phase after administration of chemotherapy
Study Regimen Phase Endpointb (% of pts)

(pt no.)
complete response
complete protection
no emesis no nausea no significant nausea
no rescue medication

Rapoport et al.[31] APR Acute 89** 92**
(425) Delayed 71** 78**
Overall 69** 76**c
CON Acute 80 84
(407) Delayed 61 67
Overall 56 62c

Warr et al.[30] APR Acute 76* 88** 80 83
(433) Delayed 55 81** 65 63
Overall 51*c 43 76** 33 61 59
CON Acute 69 77 78 80
(424) Delayed 49 69 62 60
Overall 42c 37 59 33 56 56
aPts who received chemotherapy and at least one dose of the study drug and had at least one post-treatment assessment during cycle 1.
bSee table IV for definition of endpoints.
cPrimary endpoint.
* p < 0.05, ** p < 0.001 vs CON (values not adjusted for multiplicity).

In the other study, patients with various malig- nancies were scheduled to be treated with a single dose of one or more of the following chemother- apeutic agents: any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irin- otecan, daunorubicin, or doxorubicin; intravenous cyclophosphamide <1500mg/m2; or intravenous cytarabine >1g/m2.[31] The various types of malig- nancies included breast (52% of patients), colorectal (20%), lung (13%) and ovarian cancer (4.6%).

Single-Cycle Chemotherapy
In patients with breast cancer treated with MEC, an aprepitant regimen, compared with a control regimen, was significantly more effective for the prevention of CINV, according to data from the large phase III trial.[30] Significantly (p < 0.05) more patients treated with the aprepitant regimen had an overall complete response (pri- mary endpoint) than with the control regimen alone (table VIII). Complete responses during the
acute phase (table VIII) were also significantly higher with the aprepitant regimen than with the control regimen. When the separate components of complete response were analysed, significantly (unadjusted p-value < 0.001) more recipients of the aprepitant than the control regimen reported no emesis during the overall, acute and delayed pha- ses, but there was no significant difference between the groups for the use of rescue medication for any phase (table VIII). There was no significant dif- ference between the groups during the overall phase for the percentage of patients reporting no nausea or no significant nausea.
Assessment of the impact of vomiting and nausea on the patients’ daily lives (using the FLIE questionnaire) indicated that a higher proportion of patients treated with the aprepitant than the control regimen reported no or minimal impact on daily living overall (64% vs 56%; p = 0.019), with significant differences favouring aprepitant in the vomiting domain score (86% vs

72%; p < 0.001), but not the nausea domain score (54% vs 51%).[30]
Significantly (p < 0.001) more recipients of an aprepitant than a control regimen had no emesis (primary endpoint) and a complete response dur- ing the overall phase, according to preliminary data from a large phase III trial in patients with a variety of malignancies receiving MEC (table VIII). Significantly more recipients of the aprepitant re- gimen than the control regimen had no emesis and a complete response during the acute and delayed phases (table VIII).[31]
In a smaller, single-centre trial in Chinese pa- tients with breast cancer treated with MEC, there

60

50

40

30

20

10

0

*

Cycle 1 (n = 857)

Cycle 2 (n = 734)

Aprepitant regimen Control regimen

Cycle 3 Cycle 4
(n = 683) (n = 647)

was no significant difference between the treat- ment groups for the number of patients who re- ported complete responses, complete protection, no vomiting, no significant nausea, no nausea or no rescue medication during the overall, acute or delayed phases.[32] However, the impact of vo- miting and nausea on the patients’ daily lives (assessed according to the FLIE questionnaire) for the vomiting domain was significantly less for those treated with aprepitant than those treated with the control regimen (mean score 3.40 vs 23.99; p = 0.0002), although there was no sig- nificant between-group difference for the total score or for the nausea domain.[32]

Multiple-Cycle Chemotherapy
In a multiple-cycle extension[40] of the large phase III trial in patients with breast cancer,[30] the advantage of the antiemetic effect of the aprepitant regimen over the control regimen seen in cycle 1 (complete response 51% vs 43%; p = 0.015) was maintained throughout the additional three cycles of MEC (figure 2).

4.1.3Special Populations
A randomized, double-blind, multicentre trial compared the efficacy of an aprepitant regimen (aprepitant plus dexamethasone plus ondansetron) with a control regimen (dexamethasone plus on- dansetron) in the prevention of CINV in adoles- cent patients (n = 46) scheduled for treatment with emetogenic chemotherapy or a previously intoler- able chemotherapy due to CINV.[16] Four patients
Fig. 2. Estimated probability of complete response in an individual cycle in the 5 days after treatment with moderately emetogenic chemotherapy (MEC) in breast cancer patients (pts).[40] Pts (n = 744) who had completed one cycle of chemotherapy in a randomized, double-blind, multicentre study (866 pts initially randomized) entered the multiple-cycle, extension study during which they received an additional three cycles of MEC and an aprepitant (aprepitant plus dexamethasone plus ondansetron) or control regimen (dexa- methasone plus ondansetron; see table VI for details of dosage and days of administration) to prevent nausea and emesis. Analyses are based on the modified intent-to-treat population and used a transi- tional probabilities approach. * p = 0.015; statistical analyses not re- ported for cycles 2–4.

also received open-label treatment with the apre- pitant regimen.
Specific details of each regimen and the dosage of each of the antiemetic agents involved are pre- sented in table IX. Patients were aged 11–19 years with confirmed malignancy and a Karnofsky score ‡60. Most patients had bone sarcoma (53% treated with the aprepitant regimen and 83% treated with the control regimen).[16]
Rates of complete response in the overall, acute and delayed phase were 29%, 61% and 36% in recipients of the aprepitant regimen and 6%, 39% and 6% with the control regimen, with no statistically significant difference between the two treatment groups.[16] Rates of no emesis and no use of rescue medication (during the acute, delayed and overall phase), and overall rates of no nausea were not significantly different be- tween the two treatment groups. However, the study was not sufficiently powered to demon- strate a between-group difference in efficacy and the lack of statistical significance may have been due to the small sample size.

Table IX. Aprepitant (APR) or control (CON) regimens used in a randomized, double-blind multicentre trial in adolescent patients aged 11–19 years treated with emetogenic chemotherapy. APR and DEX were administered orally and OND was administered intravenously
Regimen Dose [day(s) administered]
APR APR 125 mg [1]a then 80 mg od [2, 3]
DEX 8 mg [1]b then 4 mg od [2–4]
OND 0.45 mg/kg [1]
CON DEX 16 mg [1]b then 8 mg od [2–4]
OND 0.45 mg/kg [1]
aAdministered 1 h prior to chemotherapy.
bAdministered 30 minutes prior to chemotherapy.
DEX = dexamethasone; od = once daily; OND = ondansetron.

4.2Postoperative Nausea and Vomiting (PONV)
The efficacy of aprepitant was compared with that of ondansetron for the prevention of PONV in randomized, double-blind, multicentre, phase III trials in patients undergoing open, ab- dominal surgery under general anaesthesia.[41,42]
This section focuses on data pertaining to the approved 40 mg dose of aprepitant.
Patients (n = 922[41] and 805[42]) were random- ized to receive a single dose of oral aprepitant 40 or 125 mg (administered with 50 mL of water 1–3 hours before anaesthesia), or an intravenous dose of ondansetron 4 mg (administered immediately before induction of anaesthesia). Patients could not receive additional prophylactic antiemetics within 24 hours pre-operatively, intra-operatively or postoperatively, although patients could re- ceive rescue antiemetics for established PONV.
Patients were aged ‡18 years with an American Society of Anesthesiologists physical status class of I–III and were scheduled to undergo open abdom- inal surgery requiring an overnight stay in hospital and to receive volatile agent-based anaesthesia in- cluding nitrous oxide. Patients who had vomited within the previous 24 hours or due to an organic aetiology were excluded from the trials.[41,42]
Of the 564 patients who received aprepitant 40 mg in both these trials,[41,42] 92% were women (who were mainly undergoing gynaecological surgery), 58% were White, 13% Hispanic American, 7% multi-racial, 14% Black, 6% Asian and

2% were from other races.[6] The mean age of patients treated with aprepitant 40 mg was 46.1 years (range 19–84 years).[6]
A primary efficacy endpoint in both trials was the complete response rate (see table IV for defi- nition) in the 24 hours after surgery in the mITT population (866[41] and 733[42] patients). A co- primary endpoint in one of the trials was the rate of no vomiting in the 24 hours after surgery.[41]
One trial assessed the noninferiority of aprepitant compared with ondansetron;[41] noninferiority was achieved if the lower bound for the one-sided 95% CI for the odds ratio of aprepitant versus ondansetron was >0.65.
One of the studies failed to met the primary hypothesis that aprepitant was superior to ondan- setron, as measured by the proportion of patients with complete response.[42] However, the second study established that a single dose of aprepitant 40 mg was noninferior to ondansetron in achieving complete response (odds ratio 1.4; lower bound of the one-sided 95% CI was 1.04).[41]
Aprepitant 40 mg was significantly more ef- fective than ondansetron at preventing vomiting at 24 and 48 hours after surgery in both studies (p < 0.001; table X).[41,42] Moreover, during the first 48 hours after surgery, aprepitant 40 mg, compared with ondansetron, delayed the time to the first vomiting episode (p < 0.001) in both stu- dies. More aprepitant 40 mg than ondansetron recipients had no significant nausea (p < 0.05; table X) in one of the studies.[41] There was no significant between-group difference in the num- ber of patients who did not require rescue medi- cation (table X) in either of the studies.
According to post hoc analyses of pooled data from both of these trials, aprepitant 40 mg was significantly more effective than ondansetron for each of the five endpoints (figure 3) in the 24 hours after surgery, including: no significant nausea; no nausea; no vomiting; no nausea and no vomiting; and no nausea, no vomiting and no use of rescue medication.[43]

5.Pharmacoeconomic Considerations

A number of analyses have examined the cost effectiveness of an aprepitant regimen relative to

Table X. Clinical efficacy of oral aprepitant (APR) compared with that of ondansetron (OND) in the prevention of postoperative nausea and vomiting in surgical patients (pts) in two, randomized, double-blind, multicentre, phase III trials.[41,42] Pts received a single oral dose of APR 40 or 125 mg (administered with 50 mL of water 1–3 hours before anaesthesia), or an intravenous dose of OND 4 mg (administered immediately before induction of anaesthesia)
Study Dose (mg) No. of pts Complete No vomiting (% of pts) No rescue No significant

(mITT)
responsea (% of pts) 0–24 hb
0–24 h 0–48 h
medication (% of pts) 0–24 h
nauseac (% of pts) 0–24 h

Diemunsch et al.[41] APR 40 293 64d 84** 82** 67 62*
APR 125 293 63 86** 85** 65 60
OND 4 280 55 71 66 63 53
Gan et al.[42] APR 40 248 45 90** 85**e 45 50
APR 125 239 43 95** 90**f 44 49

OND 4 246 42
aDefined as no vomiting and no use of rescue medication.
bPrimary endpoint.
74 67e 46 43

cPeak verbal rating scores of 0–4 on an 11-point scale; 0 (no nausea) to 10 (nausea as bad as could be).
dNoninferior to OND (lower bound of one-sided 95% CI >0.65).
eData obtained from the US prescribing information.[6]
fEstimated from a graph.
mITT = modified intent-to-treat population; * p < 0.05, ** p < 0.001 vs OND.

a control regimen for the prevention of CINV in patients treated with HEC or MEC from a healthcare payer perspective.[44-46] Dosages of the agents involved in the regimens from the studies involved are presented in table V (HEC) and ta- ble VI (MEC). Further details of the methodol- ogy of the pharmacoeconomic studies are shown in table XI.
An aprepitant regimen compared with a con- trol regimen was considered to be cost effective with regard to the cost per quality-adjusted life- year (QALY) in the prevention of CINV in two European studies,[44,45] although not according to a US analysis.[46] In the Belgian study,[45] an aprepitant regimen was predicted to dominate a control regimen for both MEC and HEC (i.e. were less expensive and more effective) based on incremental costs per QALY gained in both the trial-based and real-life approach that were tested in the model (year of costing 2005). The aprepi- tant regimen was estimated to be cost effective relative to the control regimen in the prevention of CINV during HEC in the German study, if a threshold value of h43 600 per QALY gained was used (year of costing 2004).[44] However, in the US analysis,[46] the incremental cost per QALY
gained for the aprepitant regimen relative to the control regimen administered over five cycles of HEC exceeded the commonly accepted cost- effectiveness threshold of $US50 000 per QALY (year of costing 2005).
In the European studies, analyses demon- strated that the results were most sensitive to changes in the costs of hospitalization, rescue medication (German study[44]) and the cost of ondansetron (Belgian study). In the US study, sensitivity analyses indicated that the aprepitant regimen may be cost effective relative to the control regimen when rescue medication is costly or where the risk of delayed CINV is high.[46]
Pharmacoeconomic analyses, including those of aprepitant regimens, are subject to a number of limitations. Pharmacoeconomic analyses based on clinical trials extrapolate the results of such trials to the general population; however, patient populations, rates of compliance and major out- comes in clinical trials may differ from those ob- served in real-life practice. Modelled analyses, such as those presented in this section, rely on a number of assumptions and use data from a va- riety of sources. Results of pharmacoecono- mic analyses may not be applicable to other

Aprepitant 40 mg (n = 541) Aprepitant 125 mg (n = 532) Ondansetron 4 mg (n = 526)
100

90

80

70

60

50

40

30

20

10

0

No significant nausea
No nausea (VRS = 0)
No vomiting No nausea and
no vomiting
No nausea, no vomiting,

(VRS 0–4) no rescue medication

Fig. 3. Post hoc analysis of efficacy of aprepitant compared with ondansetron in the prevention of nausea and vomiting in the 24 hours after patients (pts) had undergone open abdominal surgery.[43] Combined analysis of data from the modified intent-to-treat population (n = 1559) from two randomized, double-blind trials.[41,42] Pts were randomized to receive a single dose of oral aprepitant 40 or 125 mg (administered with 50 mL of water 1–3 hours before anaesthesia), or an intravenous dose of ondansetron 4 mg (administered immediately before induction of anaesthesia). VRS = verbal rating score; an 11-point scale ranging from no nausea (0) to nausea as bad as it could be (10); * p < 0.05, ** p < 0.01, *** p < 0.001 vs ondansetron.

geographical regions because of differences in healthcare systems, medical practice and unit costs.

6.Tolerability

6.1CINV

The tolerability of an antiemetic regimen containing oral aprepitant (125 mg on day 1 then 80 mg once daily on days 2 and 3) has been in- vestigated in patients receiving single or multiple cycles of HEC or MEC who participated in the clinical trials discussed in section 4. Aprepitant was administered in combination with ondanse- tron and dexamethasone (see table V and table VI for further details). Pooled analyses of the trials[6,13,35] (including those reported in the manufacturer’s US prescribing information[6]
and the EU summary of product character- istics[13]) are also discussed in this section.
6.1.1Highly Emetogenic Chemotherapy
An aprepitant regimen was generally well tol- erated in patients receiving a single cycle of HEC (cisplatin based), with most adverse events being mild to moderate in intensity.[6,27-29] The incidence of adverse events in recipients of an aprepitant re- gimen was similar to that in recipients of the con- trol regimen (dexamethasone plus ondansetron).
According to a combined analysis[6,35] of two well controlled trials[27,28] in patients receiving one cycle of HEC, drug-related clinical adverse events were reported in »17% of the 544 re- cipients of the aprepitant regimen and »13% of the 550 recipients of the control regimen. Treat- ment was discontinued due to a clinical adverse event in 8% of patients treated with the aprepi- tant regimen and 6% of patients treated with the control regimen.[35] The adverse events that were reported in ‡10% of recipients of aprepitant were asthenia/fatigue, nausea, hiccups, constipation, diarrhoea and anorexia (see figure 4).

Serious adverse events were reported in 13% and 14% of recipients of the aprepitant or control regimen.[35] Serious adverse events (regardless of causality) that were reported in the two studies included bradycardia, disorientation and perfo- rated duodenal ulcer.[6]
Laboratory adverse events that occurred in ‡3% of recipients of the aprepitant or control regimen included increases in ALT (6% vs 4.3%), increases in AST (3.0% vs 1.3%), increases in blood urea nitrogen (4.7% vs 3.5%), increases in serum creatinine (3.7% vs 4.3%) and proteinuria (6.8% vs 5.3%).[6] The adverse experiences asso- ciated with the increases in ALT or AST were generally mild or moderate in intensity.
The tolerability profiles of an aprepitant regi- men and a control regimen during the multiple- cycle extension (up to five additional cycles of

chemotherapy) were generally similar to those observed after one cycle of HEC.[13] Drug-related clinical adverse events occurred in 6% and 4% of recipients of the aprepitant (n = 413) or control (n = 438) regimens during cycles 2–6.[36]

6.1.2Moderately Emetogenic Chemotherapy
An aprepitant regimen was generally well tol- erated in a studies in 866 evaluable patients with breast cancer[30] or 848 evaluable patients with various malignancies[31] receiving a single cycle of MEC.
The adverse event profile of an aprepitant re- gimen in patients receiving MEC was generally similar to that reported in patients receiving HEC. In recipients of an aprepitant regimen or a control regimen, the incidence of drug-related adverse events was 21.5% and 19.6% in the study

Table XI. Cost effectiveness of an aprepitant (APR) regimen (APR plus dexamethasone plus ondansetron) compared with a control (CON) regimen (dexamethasone plus ondansetron) in the prevention of chemotherapy-induced nausea and vomiting. Dosages of the agents involved in these regimens are presented in table V (highly emetogenic chemotherapy [HEC]) and table VI (moderately emetogenic chemotherapy [MEC]). All analyses are from a healthcare payer perspective
Lordick et al.[44] Annemans et al.[45] Moore et al.[46]
Methodology
Chemotherapy type HEC HEC; MEC HEC

Source of efficacy data
Clinical trials[27,28,36]
HEC[29] and MEC[40] clinical trials (trial-based); longitudinal hospital database (real-life based)
Clinical trial[27]

Time horizon
5 days after a single cycle of chemotherapy
Four cycles (21 days) of chemotherapy
Five cycles (28-day) of chemotherapy

Discounting Undiscounted NR NR
Study design Decision analytical Decision analytical Markov
Year of costing 2004 2005 2005
Country of study Germany Belgium US

Costs
Physician and hospitalization; antiemetic prophylaxis; rescue medication; unit costs for Germany were applied
Physician and hospitalization; antiemetic prophylaxis; rescue medication; unit costs for Germany were used and then adapted for Belgium
Clinic visit; laboratory costs antiemetic prophylaxis; rescue medication; unit costs for US were used

Incremental results (APR vs CON)
QALYs gained HEC 0.0017 0.003 (trial-based and real-life based) 0.007
QALYs gained MEC 0.014 (trial-based and real-life based)

Costs HEC
h49.60
-h66.84 (trial-based) and
-h74.62 (real-life based)
$US682

Costs MEC
-h17.95 (trial-based) and
-h21.70 (real-life based)

Cost per QALY gained
h28 891
APR is dominant to CON for HEC and MEC (trial-based and real-life based)
$US97 429

NR = not reported; QALY = quality-adjusted life-year.

a

20
Aprepitant regimen (n = 544) Control regimen (n = 550)

18
16
14
12
10
8
6
4
2
0
Asthenia/fatigue Nausea HiccupsConstipationDiarrhoea AnorexiaHeadacheVomitingDizzinessDehydrationHeartburn
b

30
Aprepitant regimen (n = 438) Control regimen (n = 428)

25

20

15

10

5

0
Alopecia FatigueHeadacheConstipationNeutropeniaDyspepsia NauseaDiarrhoeaStomatitis AnorexiaInsomnia

Fig. 4. Tolerability of an aprepitant regimen in patients (pts) treated with one cycle of emetogenic chemotherapy. Pts received a control regimen (ondansetron plus dexamethasone) or an aprepitant regimen (aprepitant plus ondansetron plus dexamethasone). Placebo tablets or capsules were administered to maintain blinding. Adverse events reported in ‡5% of either treatment regimen are shown. Nausea or vomiting were considered to be adverse events if they occurred after day 5 of the study or at any time if they were serious, drug related or resulted in discontinuation. Data were obtained from the manufacturer’s US prescribing information.[6] Statistical analyses not reported. (a) A pooled analysis of two randomized, double-blind, multicentre trials in 1094 evaluable cancer pts treated with highly emetogenic (cisplatin-based) chemotherapy.[6] See table V for further details of dosage and days of administration of each antiemetic agent. (b) A randomized, double-blind, multicentre trial in 866 evaluable pts with breast cancer receiving moderately emetogenic chemotherapy.[6] See table VI for further details of dosage and days of administration of each antiemetic agent.

involving breast cancer patients,[30] and 7.2% and 9.3% in the study involving of the patients with various malignancies.[31] Most adverse events were mild to moderate in intensity. Less than 5%
of patients reported serious adverse events, with the incidence being similar with the aprepitant or control regimen.[30] The incidences of dis- continuations due to adverse events were 1.6%

and 1.2% in the study involving patients with breast cancer,[30] and 0.2% and 0.5% in the study involving patients with various cancers.[31]
Adverse events that were reported in ‡5% of recipients of aprepitant included alopecia, fa- tigue, headache, constipation and dyspepsia,[30,31]
with the incidence of these adverse events gen- erally being similar to that in the control regimen (see figure 4 for the aprepitant tolerability profile in patients with breast cancer). In the trial in pa- tients with breast cancer,[6] laboratory adverse events that occurred in ‡3% of recipients of the aprepitant or control regimen included decreases in haemoglobin (2.3% vs 4.7%) and decreases in white blood cell count (9.3% vs 9.0%).
The tolerability profiles of an aprepitant regi- men and a control regimen during the multiple- cycle extension study[40] in patients with breast cancer (n = 744) administered up to five addi- tional cycles of MEC were generally similar to those observed after one cycle of MEC.

6.2PONV

The tolerability of a single oral dose of apre- pitant 40 mg has been compared with that of a single intravenous dose of ondansetron in pa- tients undergoing open, abdominal surgery who participated in two large, well controlled studies discussed in section 4.[41,42] Tolerability data have also been obtained from the pooled analyses of these trials reported in the aprepitant manu- facturer’s US prescribing information[6] and the EU summary of product characteristics.[13] In the combined analysis, 564 evaluable patients were administered aprepitant 40 mg and 538 eva- luable patients were administered ondansetron 4 mg.
Drug-related clinical adverse experiences were reported in 6% of the aprepitant 40 mg recipients and 4% of the ondansetron recipients.[41,42] Most adverse events were mild to moderate in intensity. According to the combined analysis,[6] the toler- ability profiles of aprepitant 40 mg and ondanse- tron 4 mg were similar, with the most commonly occurring adverse events (‡5% of patients) being constipation (8.5% vs 7.6%), nausea (8.5% vs 8.6%), pruritus (7.6% vs 8.4%), pyrexia (5.9% vs

10.6%), hypotension (5.7% vs 4.6%), headache (5.0% vs 6.5%) and flatulence (4.1% vs 5.8%). A laboratory adverse event that occurred in ‡3% of patients was a decrease in haemoglobin (3.8% vs 4.2%). Increases in ALT were reported in 1.1% of recipients of aprepitant 40 mg and 1.0% of re- cipients of ondansetron 4 mg.

7.Dosage and Administration Aprepitant, in combination with other anti-
emetics, is indicated in various markets (includ- ing the US[6] and Europe[13]):
ti for the prevention of nausea and vomiting associated with initial and repeat courses of MEC;
ti for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC (including high-dose cisplatin);
ti for the prevention of PONV.
Aprepitant is not recommended for use in paediatric patients, as safety and efficacy have not been established in this population.[6,13]
Aprepitant should not be given to pregnant pa- tients unless its use is considered essential. Apre- pitant is excreted in the milk of rats; however, it is not known if this agent is excreted in human milk. The US prescribing information notes that the decision as to whether to discontinue nursing or discontinue the aprepitant in nursing mothers should take into account the importance of the drug for the mother and the potential for serious adverse events in nursing infants and its potential for tumorigenicity in animal studies.[6] In Europe, breast feeding is not recommended during treat- ment with aprepitant.[13]
When used for the prevention of CINV, apre- pitant should be administered for 3 days as part of a combination antiemetic regimen that includes a corticosteroid and a 5-HT receptor
3 antagonist. The recommended oral aprepitant dosage is 125 mg administered 1 hour prior to the initiation of chemotherapy (day 1) and 80 mg on the mornings of days 2 and 3.[6,13]
When used for the prevention of PONV, the recommended oral dose of aprepitant is 40 mg administered within 3 hours prior to anaesthesia.[6,13]

Aprepitant should be used with caution when

Before the advent of 5-HT
3

receptor antago-

used concomitantly with drugs that are CYP3A4 substrates or inhibitors (see section 3.4).[6,13]
Aprepitant should not be coadministered with pimozide, terfenadine, astemizole or cisapride. Concomitant corticosteroid dosages should be adjusted (see section 3.4). Weak inhibition of CYP3A4 by a single dose of aprepitant 40 mg is not expected to alter the plasma levels of con- comitantly administered agents that are primarily metabolized through CYP3A4. The efficacy of aprepitant may be reduced when coadministered
nists, available antiemetics included phenothia- zines, substituted benzamides, antihistamines, butyrophenones, corticosteroids, benzodiazepines and cannabinoids.[1,4] The introduction of 5-HT
3 receptor antagonists represented a major advance in the prevention of CINV and PONV.[1,4,48] These agents (see table XII) have been effective in con- trolling acute nausea and/or vomiting and are generally well tolerated, and their inclusion in a regimen aimed at preventing acute CINV is re- commended (table XIII).[1] Although the first

by drugs that are strongly induced by CYP3A4.
generation of 5-HT
3
receptor antagonists (includ-

Patients receiving oral contraceptives should use back-up or alternative contraception while they
ing ondansetron, granisetron and dolasetron) are not generally effective in preventing delayed

are receiving aprepitant (see section 3.4).
emesis, the second-generation 5-HT
3
receptor

Administration of aprepitant to patients with severe hepatic insufficiency has not been studied; therefore, caution is advised when this agent is administered to this patient group. No dosage adjustment is required in patients with renal
antagonist palonosetron has been effective in pre- venting acute CINV (during the first 24 hours following chemotherapy), and also exhibits pro- longed efficacy to provide protection from CINV in the delayed and overall phases.[49,50] Oral forms

insufficiency.[6,13]
of 5-HT
3
receptor antagonists are as effective as

The local manufacturer’s prescribing informa- tion should be consulted for detailed information regarding contraindications, warnings, drug inter- actions, patient monitoring recommendations and use in special patient populations.

8.The Place of Aprepitant in the Prevention of Nausea and Vomiting

Nausea and vomiting cause significant pro- blems in patients recovering from surgical pro- cedures carried out under general anaesthesia and in cancer patient receiving MEC or HEC. Benefits in terms of patients’ recovery and health- related quality of life would be achieved with re- ductions in the incidence of CINV or PONV.[47]
To provide the greatest protection, antiemetic therapy should usually be administered prior to the administration of chemotherapy or prior to
intravenous forms.
Corticosteroids (especially dexamethasone) are effective in the prevention of CINV.[4,51-53] The precise mechanism of action of corticosteroids in the prevention of emesis is uncertain but may in- volve a reduction of serotonin release or activation of corticosteroid receptors in the CNS.[54] Short- term corticosteroid therapy is generally well toler- ated. Dexamethasone is effective in preventing acute and delayed nausea and vomiting and is in- cluded in most recommended preventive regimens (table XIII).

Table XII. Antiemetic agents
Class Examples
Benzodiazepines Lorazepam; olanzapine
Cannabinoids Dronabinol; nabilone
Corticosteroids Dexamethasone; methylprednisolone

surgery. When used in the prevention of CINV, the antiemetic regimen should be continued for the duration of the effect of the chemotherapy involved.[4] Since no single agent can be expected to provide complete protection against the va- rious phases of CINV, a combination of anti- emetic agents is usually administered.
Dopamine antagonists Neurokinin-1 receptor antagonists Serotonin 5-HT3
receptor antagonists
Droperidol; haloperidol; metoclopramide; prochlorperazine; promethazine Aprepitant; fosaprepitant

Dolasetron; granisetron; ondansetron; palonosetron; ramosetron and tropisetron

Table XIII. Guideline recommendations for the prevention of chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV) in adult patients (pts). CINV guidelines for highly emetic chemotherapy (HEC) and moderately emetic chemotherapy (MEC) are presented from the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the Multinational Association of Supportive Care in Cancer (MASCC) and National Comprehensive Cancer Network (NCCN). Consensus PONV guidelines from the Society for Ambulatory Anesthesia (SAMBA) are also presented
Guideline Recommendation regimena
Day 1 Day 2 onwards CINV (HEC)
ASCO[52] APR + DEX + 5-HT3 RA APR + DEX
ESMO[60] APR + COR + 5-HT3 RA APR + COR
MASCC[61] APRb + DEX + 5-HT3 RA APR + DEX
NCCN[4] APRb + DEX + 5-HT3 RAc APR + DEX – LOR
CINV (MEC)
ASCO[52] APRd + DEX + 5-HT3 RA APR – DEXd; or DEX
ESMO[60] APRd + CORe + 5-HT3 RA APR + DEXd; or CORf; or 5-HT3 RAf
MASCC[61] APRd + DEX + 5-HT3 RA APR + DEXd; or DEXf; or 5-HT3 RAf
NCCN[4] APRb,g + DEX + 5-HT3 RAc APR – DEXh; or DEX; or 5-HT3 RAc
PONV

SAMBA[62]
Combination of ‡1 (moderate risk) or ‡2 (high risk) antiemetic agents from different classesi
Another class of drugsj

aSee guidelines for recommended dosage of each agent in pts receiving HEC or MEC.
bIntravenous fosaprepitant may be substituted for APR on day 1.
cLOR + histamine receptor antagonist or a proton pump inhibitor are recommended, but optional, additions.
dPts treated with an anthracycline plus cyclophosphamide only.
eDEX is recommended in pts treated with APR.
fPts treated with MEC other than anthracycline plus cyclophosphamide.
gIn selected pts treated with MEC (e.g. carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan or methotrexate).
hIn pts treated with APR on day 1.
iRecommended agents include 5-HT3 RA, DEX or droperidol.
jRecommended agents include DEX, droperidol or promethazine, or a 5-HT3 RA for pts who did not receive prophylaxis.
5-HT3 RA = serotonin 5-HT3 receptor antagonist; APR = aprepitant; COR = corticosteroid; DEX = dexamethasone; LOR = lorazepam.

NK
1
receptor antagonists provide a different
well tolerated, with a pharmacokinetic study de-

and complementary mechanism of preventing em- monstrating its bioequivalence to aprepitant.[57]

esis to other available antiemetics. NK
1
receptor
Other NK1
receptor antagonists that are

antagonists act by blocking the binding of sub- under investigation in the prevention of CINV

stance P at the NK
1
receptor in the brainstem
and PONV include vofopitant, casopitant and

emetic centre and the GI tract. Aprepitant is the first agent in this class to be approved (including the US,[6] Canada and Europe[13]) for use in the prevention of CINV or PONV (see section 7). Aprepitant is poorly soluble in aqueous solutions and therefore is administered orally. An intra- venous form of the prodrug of aprepitant (fosaprepitant) has recently been approved by the US FDA and European Medicines Agency as a substitute for oral aprepitant on day 1 of a standard CINV prevention regimen.[13,55,56] Fosaprepitant is
rolapitant.[58,59]
Treatment guidelines for the prevention of CINV have been published by several organiza- tions including the National Comprehensive Cancer Network (NCCN),[4] the American Society of Clinical Oncology,[52] the European Society for Medical Oncology[60] the Multi- national Association of Supportive Care in Can- cer[61] (table XIII). For cancer patients receiving HEC, the guidelines generally recommend the administration of 3 days of aprepitant (or a single

intravenous dose of the prodrug fosaprepitant) in the antiemetic regimen; a corticosteroid (gen- erally dexamethasone) plus any 5-HT3 receptor antagonist are also recommended agents for in- clusion. In cancer patients treated with MEC, current guidelines also recommend the adminis- tration of 3 days of aprepitant in selected pa- tients. Some guidelines[52,60,61] restrict the use of this agent to patients to be treated with an an- thracycline plus cyclophosphamide but the NCCN guidelines suggesting this agent should also be used in patients to be treated with other chemotherapies of moderate emetic risk (e.g. carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate). If apre- pitant (administered over 3 days) is used in patients treated with MEC, then generally the guidelines recommend its use in combination

achievement of a complete response in both the acute and delayed phases. This preventative effi- cacy was maintained across multiple cycles of chemotherapy. The addition of aprepitant to a regimen containing ondansetron and dexa- methasone significantly reduced the impact of CINV on the daily lives of the patients.
Similarly, aprepitant in combination with on- dansetron and dexamethasone was more effective than ondansetron and dexamethasone in achiev- ing a complete response and preventing emesis in the 5 days after administration of a single cycle of MEC in phase III studies involving patients with breast cancer or various malignancies. The ad- vantage of the antiemetic effect of the aprepitant regimen over the control regimen seen after the first cycle of MEC was maintained throughout an additional three cycles in a multiple-cycle exten-

with dexamethasone and a 5-HT3 antagonist.
receptor
sion of the large phase III trial in patients with breast cancer (section 4.1.2).

Comparison of prophylactic regimens in the prevention of CINV or PONV should take into account the effect of rescue medication on either nausea or vomiting. Once rescue medication has been administered, the lack of nausea and/or vo- miting may be due to the prophylactic medica- tion, the rescue medication or both. Thus, the trials that investigated the efficacy of aprepitant regimens generally used complete response (no emesis and no rescue medication) as the primary endpoint. Phase III trials have established (using this primary endpoint) that an aprepitant regi- men was effective in the prevention of CINV and PONV.
Early studies involving aprepitant demon- strated that the triple combination of aprepitant with a corticosteroid and a 5-HT3 receptor anta- gonist was more effective than the dual combi- nation of a corticosteroid plus another agent in
The control of nausea in patients receiving MEC or HEC remains a significant problem.[2]
The role of the 3-day aprepitant regimen in the prevention of nausea is unclear, with data from phase III studies being inconsistent. There was a significant difference between the aprepitant and control regimen in the number of patients with no nausea in the delayed and overall phases (table VII) in one[28] of the identical phase III studies in patients treated with HEC (section 4.1.1). In a phase III trial in breast patients receiving MEC,[30] there was no improvement in nausea when aprepitant was added to dexamethasone plus ondansetron (section 4.1.2). Given their dif- fering mechanism of action, cannabinoids may be useful in chemotherapy-induced nausea;[2] how- ever, trials that investigate the combination of a cannabinoid and aprepitant in the prevention of CINV have yet to be conducted.

the prevention of cisplatin-induced emesis.[63,64]
Since palonosetron is the only 5-HT
3
receptor

Subsequent large, phase III trials in patients with cancer (section 4.1.1) confirmed that aprepitant in combination with ondansetron and dexa- methasone was more effective than a regimen of ondansetron and dexamethasone in achieving a complete response in the 5 days after adminis- tration of a single cycle of cisplatin-based HEC. Moreover, aprepitant was effective in the
antagonist that is effective in preventing CINV during both the acute and delayed phases, phase I and II studies have investigated the efficacy of various regimens that combine this agent with aprepitant. An early phase II study found that a regimen of aprepitant (days 1–3) plus dexa- methasone (days 1–3) plus palonosetron (day 1) was effective in patients (n = 58) receiving various

moderately to moderate-highly emetogenic chemo- therapies (complete response rate 78%).[65] The recent NCCN guidelines recommend the use of

Aprepitant is generally well tolerated in pa- tients when used in the prevention of CINV or PONV (section 6). In cancer patients receiving

palonosetron as the preferred 5-HT
3
receptor anta-
single or multiple cycles of HEC or MEC, the

gonist (in combination with dexamethasone and aprepitant) in patients receiving HEC.[4] This recommendation was based on the results of a randomized study;[66] however, this study used a higher than recommended dosage of palonosetron and aprepitant was not included. In a pilot study in patients treated with HEC and aprepitant plus dexamethasone (days 1–4) plus palonosetron (day 1), a single dose of aprepitant 125mg on day 1 displayed similar effectiveness to aprepitant ad- ministered as a 125mg dose on day 1 followed by 80mg on days 2–3.[67] Moreover, a single-day regi- men consisting of oral aprepitant 285mg plus oral dexamethasone plus intravenous palonosetron was effective (51% overall complete response) in 41 pa- tients with breast cancer receiving MEC.[68] Phase III studies in patients receiving HEC or MEC that investigated the efficacy of a single-day regimen of this three-drug combination are warranted.
An aprepitant regimen compared with a con- trol regimen was considered to be cost effective with regard to the cost per QALY in the preven- tion of CINV in two European studies, although not according to a US analysis (see section 5). In the European studies, the results were most sen- sitive to changes in the costs of hospitalization, rescue medication (German study) and the cost of ondansetron (Belgian study). In the US study, sensitivity analysis indicated that the aprepitant regimen may be cost effective relative to the control regimen when rescue medication is costly or where the risk of delayed CINV is high.
A single dose of oral aprepitant 40 mg was as effective as ondansetron in preventing PONV (assessed according to complete response in the 24 hours after surgery) in patients who had un- dergone general open abdominal surgery in two phase III studies (section 4.2). Aprepitant was significantly more effective than ondansetron at preventing vomiting in the 24 and 48 hours after surgery in both studies (p < 0.001). During the 48 hours after surgery, aprepitant compared with ondansetron, delayed the time to the first vomit- ing episode (p < 0.001) in both studies.
incidence of adverse events in recipients of an aprepitant regimen was similar to that in re- cipients of the control regimen. Commonly re- ported adverse events were asthenia/fatigue, nausea, hiccups, constipation, diarrhoea and an- orexia. The incidence of adverse events with a single oral dose of aprepitant was similar to that with a single intravenous dose of ondansetron when these agents were used in the prevention of PONV. Commonly reported adverse events were similar to those when an aprepitant regimen was used in the prevention of CINV and included constipation, nausea, pruritus, pyrexia, hypo- tension, headache and flatulence.
Aprepitant is metabolised by CYP3A4. More- over, aprepitant is also an inhibitor of CYP3A4 and an inducer of both CYP3A4 and CYP2C9. Consequently, aprepitant can cause a number of drug interactions (see section 3.4). The interactions tend to be more significant when the coadminis- tered drug is administered orally rather than through the intravenous route due to first-pass metabolism. The manufacturer notes that caution should be exercised when aprepitant is co- administered with a number of agents including chemotherapeutic agents, with some drugs being contraindicated due to the interaction potential of aprepitant (see section 3.4 and section 7).
The prevention of nausea and vomiting involves a complex interaction between multiple organs and multiple neurotransmitters. Continued research is needed to provide the most effective antiemetic regimen. Such a regimen is likely to involve a combination of various antiemetic agents with different mechanisms of action. In this regard, re- search is warranted to clarify the role of aprepitant, when used alone or in combination with various other antiemetic agents, in various clinical situa- tions including bone marrow transplantation, multiple-day chemotherapy regimens and radio- therapy-induced nausea.
In conclusion, when combined with a standard regimen of a corticosteroid (dexamethasone) and a serotonin 5-HT3 receptor antagonist (ondan-

setron), oral aprepitant (125 mg on day 1 then 80 mg once daily on days 2 and 3) was effective in the prevention of acute and delayed CINV asso- ciated with single or multiple cycles of HEC. This aprepitant regimen was also effective in the pre- vention of CINV in patients treated with single or multiple doses of MEC. A single oral dose of aprepitant 40 mg administered prior to patients undergoing abdominal surgery was also effective in the prevention of PONV. Aprepitant was generally well tolerated. Aprepitant is a re- commended option for the treatment of PONV, and when combined with a corticosteroid and 5-HT receptor antagonist is a recommended
3
regimen for the treatment of CINV.

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manu- facturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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Correspondence: Monique P. Curran, Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand. E-mail: [email protected]