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Aprepitant for the prevention of nausea and vomiting associated with chemotherapy and postoperative recovery Jennifer LaRusso, Scott A Waldman and Walter K Kraft† CONTENTS Mechanism & classification of nausea & vomiting Pharmacotherapy for CINV & PONV Pharmacokinetics of aprepitant Pharmacodynamics of aprepitant Drug interactions Clinical efficacy Postmarketing surveillance Safety & tolerability Regulatory affairs Conclusion Expert commentary & five-year view Financial & competing interests disclosure Key issues References Affiliations †
Author for correspondence Thomas Jefferson University, Department of Pharmacology and Experimental Therapeutics,132 South 10th Street, 1170 Main, Philadelphia, PA, USA Tel.: +1 215 955 9077 Fax: +1 215 955 5681 [email protected]
KEYWORDS: antiemetic, aprepitant, chemotherapy-induced nausea and vomiting, neurokinin-1, postoperative nausea and vomiting, substance P
Chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV) can negatively impact patient quality of life, functional performance and activities of daily living. Although the development of serotonin receptor antagonists has greatly improved the control of acute emesis, delayed CINV remains a significant clinical issue. Aprepitant (Emend ®) is the first commercially available drug from a new class of agents, the neurokinin-1 receptor antagonists. Elucidation of its mechanism of action has produced a greater understanding of the pathophysiology of nausea and vomiting. Oral aprepitant, in combination with a selective serotonin (5-HT3) receptor antagonist and corticosteroids, is indicated for the prevention of acute and delayed nausea and vomiting associated with highly and moderately emetogenic chemotherapy in adults. Aprepitant alone or in combination only with dexamethasone does not optimally control acute emesis compared with triple combination therapy. By contrast, aprepitant as monotherapy is indicated for the prevention of PONV. Aprepitant represents an emerging class of agents and its addition to standard therapy provides an advanced benefit in the prevention and treatment of CINV and PONV. Investigations of aprepitant for other indications are ongoing. Expert Rev. Clin. Pharmacol. 1(1), 27–37 (2008)
Chemotherapy-induced nausea and vomiting (CINV) is a major problem for many cancer patients. Although significant progress has been made in multimodal approaches to prevention, patients frequently cite nausea and vomiting as one of the most unpleasant and disabling side effects of chemotherapy [1,2]. These adverse effects can negatively impact quality of life and activities of daily living . Similarly, postoperative nausea and vomiting (PONV) is the most commonly reported patient fear before elective surgery . Indeed, PONV is among the most frequently occurring postoperative complications. Effective antiemetic strategies employ multiple pharmacologic targets. Recent advances have significantly improved control of these distressing side effects. Aprepitant (Emend®; 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluoro-phenyl)-410.1586/175124184.108.40.206
morpholinyl]methyl]-1,2-dihydro-3H-1,2,4triazol-3-one; MK-0869; L-754,030) is the first commercially available drug from a new class of agents, the neurokinin (NK)-1 receptor antagonists (FIGURE 1) . Aprepitant is approved by the US FDA and EMEA for the prevention of CINV and PONV. Oral aprepitant, in combination with a 5-hydroxytryptamine (5-HT3) receptor antagonist and corticosteroids, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly and moderately emetogenic chemotherapy in adults . Aprepitant as monotherapy is indicated for the prevention of PONV. Aprepitant has a novel mechanism of action compared with existing antiemetic therapies and thus is particularly attractive for use in combination therapy, especially in light of the failure rate of existing drugs to fully prevent CINV or PONV.
© 2008 Future Drugs Ltd
LaRusso, Waldman & Kraft
Mechanism & classification of nausea & vomiting
Emesis has a physiological role as a defense mechanism mediated by a somato–autonomic nerve reflex, which is located in the lateral reticular formation of the medulla oblongata. There are different pathways that generate the emetic response, including the chemoreceptor trigger zone, vestibular nuclei and visceral vagal afferent nerves . Various neurotransmitters play a role in each pathway, including histamine, dopamine, serotonin, substance P and muscarinic cholinergic neurotransmitters, depending upon the emetogenic trigger . Substance P is a ligand for the NK-1 receptor. An enhanced understanding of the pathophysiology of nausea and vomiting as a dual pathway of central and peripheral involvement has been obtained from the capacity of aprepitant to antagonize the effects of substance P by binding competitively and selectively to the NK-1 receptor . Chemotherapy-induced nausea & vomiting
CINV can be categorized under five distinct classifications: acute CINV, delayed CINV, anticipatory CINV, breakthrough CINV and refractory CINV . Acute CINV is defined as nausea and vomiting arising within the first 24 h succeeding chemotherapy administration. Following the administration of cisplatin, a highly emetogenic chemotherapy, acute emesis usually begins within 1–2 h of chemotherapy and peaks in the first 4–6 h. Delayed CINV occurs 24 h after chemotherapy administration and may persist for a number of days . This emetic response may vary depending upon the emetogenicity of the chemotherapy agent. Anticipatory CINV is a learned behavioral response that occurs prior to treatment. This conditioned response is observed in 18–57% of patients and is secondary to poorly controlled nausea and vomiting during previous chemotherapy . Behavioral modifications and nonpharmacologic approaches have been employed to treat this type of emesis. Patients with breakthrough CINV experience symptoms, despite being treated with prophylactic antiemetics, and usually require rescue therapy . Refractory CINV constitutes nausea and vomiting associated with chemotherapy, despite antiemetic prophylaxis or rescue therapy. The possibility of the development of CINV is influenced by individual risk factors and the emetogenicity of the chemotherapy drug administered. Younger patients and those with a history of anxiety or motion sickness are at higher risk of CINV . Patients with a history of heavy alcohol consumption are at lower risk of CINV. Gender is an important independent risk factor for CINV, with female patients more likely to experience severe emesis, especially those who had emesis during a past pregnancy . Chemotherapeutic agents are associated with varying degrees of emetic risk. Classification of these drugs into four emetic risk categories has facilitated evaluation of therapeutic utility and selection of the appropriate antiemetic regimen . Chemotherapeutic agents with the highest emetic potential (>90% encounter emesis without effective prophylaxis) include cisplatin, high-dose cyclophosphamide, dactinomycin, dacarbazine,
carmustine, streptozotocin and nitrogen mustard. Drugs that are considered to have a moderate emetic risk (>30–90%) are carboplatin, irinotecan, anthracyclines, high-dose cytarabine, ifosfamide, low-dose cyclophosphamide and oxaliplatin. The taxanes, etoposide, cetuximab, trastuzumab, pemetrexed, gemcitabine, low-dose cytarabine, 5-fluorouracil (5FU), bortezomib and methotrexate fall into the low-emetic-risk category (10–30%), whereas bevacizumab, busulfan, fludarabine, rituximab, bleomycin and the vinca alkaloids have a minimal emetic risk (9). Aprepitant is not renally excreted and patients with renal insufficiency or end-stage renal disease also do not require dose adjustments. The pharmacokinetics of aprepitant are not altered by dialysis . The modest pharmacokinetic changes of aprepitant evidenced in gender, age and race are considered clinically insignificant and do not require dose adjustments. Formal pharmacokinetic studies have not been performed in the pediatric population, although there are case reports of use in adolescents . Pharmacodynamics of aprepitant
Aprepitant has a high affinity for NK-1 receptors and little or no affinity for NK-2 and NK-3 receptors or the receptors (serotonin, dopamine and corticosteroid) targeted by other antiemetics. Animal and human PET studies demonstrate that aprepitant crosses the blood–brain barrier and competitively binds the NK-1 receptors, antagonizing the effects of substance P in the CNS . Dosages of as little as 40 mg/day are correlated with a receptor occupancy of at least 90%. Drug interactions
Since aprepitant is both a substrate and dose-dependent inhibitor of CYP3A4, co-administration of aprepitant with agents metabolized by CYP3A4 may increase plasma concentrations of those drugs. Methylprednisolone, dexamethasone and midazolam exhibit a two- to threefold increase in area under the plasma concentration–time curve when administered with aprepitant because of the moderate inhibition effect of aprepitant at the dosage of 125 mg on day 1, followed by 80 mg on days 2 and 3 of a CINV regimen (125 mg/80 mg) [34,35]. This interaction is the basis for the recommendation in current consensus guidelines of decreasing steroids when administered with aprepitant. Concomitant administration of aprepitant with a CYP2C9 substrate, such as warfarin, can decrease its plasma concentration because of the induction effect of aprepitant on CYP2C9, resulting in decreased prothrombin time in patients receiving chronic warfarin. As a result, prothrombin time (INR) should be closely monitored in the 2-week period following co-administration, particularly at 7–10 days . Strong inhibitors of CYP3A4 (ketoconazole, clarithromycin and ritonavir) may increase the
Clinical efficacy Phase II trials
Five Phase II trials have been conducted in patients receiving cisplatin chemotherapy (≥50 mg/m2), which is considered a highly emetogenic agent. Cocquyt et al. randomized 53 patients to receive either a single dose of the intravenous prodrug of aprepitant (L-758,298) or a single dose of intravenous ondansetron 1 h prior to cisplatin . The only significant difference in adverse events was increased diarrhea in patients receiving the NK-1 antagonist. Results demonstrated that L-758,298 and ondansetron had a similar effect on acute emesis, but L-758,298 excelled in the control of delayed emesis. Van Belle et al. examined 156 patients receiving cisplatin who were randomized to three treatment arms . Group 1 received intravenous L-758,298 plus intravenous dexamethasone on day 1 followed by oral aprepitant on days 2–5. Group 2 received the same regimen as group 1 on the first day, but placebo on days 2–5. Group 3 received intravenous ondansetron and dexamethasone on day 1, followed by placebo on days 2–5. In patients receiving the NK-1 receptor antagonist, 47–50% were without acute emesis and 63–68% were without delayed emesis, compared with 41% receiving placebo. Control of acute emesis was achieved by 84% of patients receiving ondansetron. Campos et al. confirmed the importance of 5-HT3 antagonists in the control of acute emesis and as part of triple therapy including aprepitant in both acute and delayed phases . The study randomized 351 patients receiving cisplatin chemotherapy to four different treatment groups. Group 1 received granisetron and dexamethasone on day 1 and placebo on days 2–5. Group 2 received oral aprepitant, granisetron and dexamethasone on day 2 and oral aprepitant on days 2–5. Group 3 received aprepitant on day 1, dexamethasone and placebo on day 1, followed by aprepitant on days 2–5. The final group received oral aprepitant, dexamethasone and placebo on day 1, followed by aprepitant on days 2–5. Granisetron in combination with dexamethasone was superior in the control of acute emesis. Daily dosing of oral aprepitant was effective in controlling CINV compared with placebo. Navari and coworkers conducted a three-arm trial focused on antiemetic combinations . All 159 patients received intravenous granisetron and oral dexamethasone prior to cisplatin. Patients were randomized to three groups. Groups 1 and 2 received an oral aprepitant on day 1. Group 1 continued to receive aprepitant on days 2–5. Group 2 and 3 received placebo
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Box 1. Aprepitant drug interactions. Aprepitant increases drug levels of: • Pimozide • Midazolam • Dexamethasone • Methylprednisolone Aprepitant has no effect on: • Digoxin • Ondansetron
78% in group 2 and 33% in group 3. There were no significant differences in therapeutic or adverse responses in groups who received oral aprepitant for 1 or 5 days. This study validated the efficacy of triple therapy in both acute and delayed CINV. Chawla et al. performed a dose-finding study of aprepitant to improve the regimen for triple therapy in 563 patients receiving cisplatin . All patients received intravenous ondansetron and dexamethasone on day 1, followed by oral dexamethasone on days 2–5. Group 1 received 125 mg of oral aprepitant on day 1, followed by 80 mg on days 2–5. Group 2 was given 40 mg of oral aprepitant on day 1 and 25 mg on days 2–5. Group 3 received oral placebo on days 1–5. This study established the use of the 125 mg/80 mg aprepitant regimen as the most effective dose.
• Dolasetron • Granisetron • Palonosetron • Docetaxel • Vinorelbine Aprepitant decreases the effect of: • Warfarin • Tolbutamide • Phenytoin • Oral contraceptives • Paroxetine • Cyclophosphamide* • Thiotepa* Drugs that lower aprepitant levels: • Rifampin • Carbamazepine • Phenytoin • Paroxetine • St John’s wort Drugs that increase aprepitant levels: • Diltiazem • Ketoconazole • Itraconazole • Troleandomycin • Clarithromycin • Ritonavir • Nelfinavir *
Modest. Adapted and modified from Prommer .
on days 2–5. Group 3 only received granisetron and oral dexamethasone. Improvement in acute emesis was observed in 92–94% of patients who were supplemented with oral aprepitant. In the delayed phase, no emesis was reported by 82% in group 1,
Phase III trials Highly emetogenic CINV
Two pivotal, randomized, Phase III trials employing highly emetogenic cisplatin (>70 mg/m2) were performed in centers from the Americas, Europe and Australia [47,48]. Both trials were randomized, double-blind, parallel, multicenter and placebo-controlled and enrolled chemotherapy-naive patients (520 in each). Patients were randomized to two groups. Group 1 received intravenous ondansetron 32 mg and oral dexamethasone 20 mg on day 1, followed by oral dexamethasone 8 mg twice daily on days 2–4. Group 2 received intravenous ondansetron 32 mg, oral aprepitant 125 mg and oral dexamethasone 12 mg on day 1, followed by oral aprepitant 80 mg on days 2–3 and oral dexamethasone 8 mg daily on days 2–4. The primary efficacy end point was complete response (no emesis and no rescue therapy for established nausea or vomiting). The addition of aprepitant relative to standard dual therapy increased complete response rates from 52 to 73% (Hesketh)  and 43 to 62% (Poli-Bigelli ; p < 0.01 in both cases). Results are summarized in TABLE 1. Similar rates of improvement were noted in the study by Schmoll et al., a third Phase III trial involving 489 cisplatin-treated patients, using similar antiemetic regimens but extending the 5-HT3 antagonist beyond day 1 to days 2–4 in the standard therapy group . In all studies, the aprepitant regimen exhibited statistically significantly improved efficacy compared with standard therapy with respect to the incidence of emesis, but not consistently with the incidence of nausea or need for rescue therapy. deWitt demonstrated that benefits were maintained through six cycles of cisplatin-based chemotherapy in patients receiving the aprepitant regimen (125 mg/80 mg) compared with those receiving standard therapy for the composite end point of no emesis and no need for rescue therapy . The aprepitantcontaining regimen prevented the composite end point in 64% of patients in the first cycle and 59% of patients in the sixth cycle. This compares to 49 and 34%, respectively, for standard therapy. Differences were statistically significant (p < 0.05). Moderately emetogenic CINV
Warr et al. conducted a Phase III double-blind study to assess the use of aprepitant in 866 breast cancer patients receiving moderately emetogenic chemotherapy . An aprepitant regimen was
LaRusso, Waldman & Kraft
Table 1. Results of pivotal Phase III studies in chemotherapy-induced nausea and vomiting: percentages of patients achieving complete response (no emesis/no rescue therapy) in Phase III trials. Author
Acute (0–24 h) Aprepitant
Delayed (24–120 h)
Overall (0–120 h)
Highly emetogenic regimen Hesketh et al.
Poli-Bigelli et al.
Schmoll et al.
Moderately emetogenic regimen Warr et al.
*p < 0.001. ‡ p = 0.015. § p ≤ 0.005. ¶ p = 0.034. # p = 0.064.
compared with a standard antiemetic regimen. For the aprepitant regimen, on day 1 prior to chemotherapy, the aprepitant group received oral aprepitant 125 mg, oral ondansetron 8 mg and oral dexamethasone 12 mg, followed by oral ondansetron 8 mg 8 h later. On days 2 and 3, oral aprepitant 80 mg was administered daily. For the standard group, on day 1, these patients received oral ondansetron 8 mg and oral dexamethasone 20 mg prior to chemotherapy and oral ondansetron 8 mg 8 h later. Ondansetron 8 mg twice daily was administered orally on days 2 and 3. The magnitude in completed response rate was more modest (42 vs 51%; p < 0.15 for superiority analysis) compared with the highly emetogenic trials, but it should be noted that a 5-HT3 antagonist was administered only on day 1 in the aprepitant group, which may have reduced effectiveness for delayed nausea and emesis. The aprepitant-containing regimen was significantly superior in the prevention of emesis, but not in the prevention of nausea or need for rescue medicine (TABLE 1). All Phase III studies demonstrated an improvement in outcomes with the addition of aprepitant to a standard regimen of a 5-HT3 antagonist and corticosteroid for the prevention of CINV. Postoperative nausea & vomiting
Two multicenter, randomized, double-blind trials were conducted to evaluate the efficacy and tolerability of aprepitant in 1658 patients for the prevention of PONV [52,53]. In patients receiving general anesthesia for open abdominal surgery, aprepitant was compared with ondansetron for the prevention of PONV. Patients were randomized to receive a preoperative dose of oral aprepitant 40 mg, oral aprepitant 125 mg or intravenous ondansetron 4 mg. The primary outcome in both studies was a complete response, defined as no emesis and no use of rescue in the time from 0 to 24 h. A study by Gan was in 805 primarily female (95%) patients . Superiority for the primary outcome was not met (45% 32
for aprepitant vs 42% for ondansetron), although aprepitant 40 mg was significantly better in preventing emesis at 0–24 h (90 vs 42% for ondansetron; p < 0.001) as well as at 0–48 h. A study by Diemunsch was originally designed to be a superiority trial for the primary outcome . Patients were again primarily (∼90%) female. As results from the Gans trial became available, and before this trial was completed or unblinded, the analysis was changed to a noninferiority with a fixed margin of greater than 0.65 for the one-sided 95% confidence interval. Complete response was seen in 65% of those taking aprepitant 40 mg and 55% for those administered ondansetron. As with the Gans trial, aprepitant 40 mg was significantly better in preventing emesis at 0–24 h (84 vs 71% for ondansetron; p < 0.001) as well as at 0–48 h. There was a smaller, but significant, improvement in complete response of no nausea and no emesis. In both studies, there was not additional clinical benefit from the use of 125 versus 40 mg of aprepitant. Postmarketing surveillance
To date, a search of the literature has not revealed reports of unusual or unexpected adverse events associated with the use of aprepitant. There has been no unanticipated pharmacovigilance signal reported. Safety & tolerability
Aprepitant has been generally well tolerated. In Phase III trials, the overall incidence of reported adverse events was similar among patients receiving aprepitant and standard therapy. In clinical trials, adverse events reported in more than 10% of aprepitant-treated patients included asthenia/fatigue, dizziness, flushing, headache, menstrual problems, hiccups, diarrhea, gastritis, nausea and anorexia [47,48,51]. Abnormal laboratory values reported in 3% or more of patients included increased alanine aminotransferase levels, mild and transient increased aspartate aminotransferase levels, increased serum
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creatinine, proteinuria and increased blood urea nitrogen. Serious adverse events reported in clinical trials regardless of causality included bradycardia, perforating duodenal ulcer and disorientation [8,26,47,48,51]. One case of Stevens-Johnson syndrome has been reported, but the patient was receiving other medications associated with that syndrome. A summary of adverse events in three of the Phase III trials for CINV are presented in TABLE 2. In healthy subjects, single doses up to 600 mg were well tolerated. In cancer patients and patients in non-CINV studies, administration of a single 375-mg dose was well tolerated. In cancer patients receiving a 250-mg daily dose, aprepitant was well tolerated. While specific information is not available for treating an aprepitant overdose, drowsiness and headache were reported in one patient who ingested 1440 mg of aprepitant . Regulatory affairs
Aprepitant was approved by the FDA in March of 2003 with the indication of the prevention of acute and delayed nausea
and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy, including high-dose cisplatin, when used in combination with other antiemetics. In October of 2005, aprepitant received approval by the FDA with the indication of the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy when used in combination with other antiemetics. In Europe, aprepitant was approved for marketing in 2003. In 2006, aprepitant received approval by the FDA and EMEA for the prevention of PONV. Aprepitant has been filed for approval in Japan by the Ono pharmaceutical company. For the treatment of acute and delayed CINV, aprepitant is administered with a 5-HT3 antagonist and dexamethasone. Recommended use is administration at a dose of 125 mg orally, 1 h prior to chemotherapy on day 1, followed by 80 mg orally in the morning on days 2 and 3 . For the prevention of PONV, the recommended oral dosage is 40 mg within 3 h prior to anesthesia induction . Aprepitant has not been studied for the treatment of established
Table 2. Percentage of patients with adverse events in Phase III chemotherapy-induce nausea and vomiting trials. Hesketh et al. 
Poli-Bigelli et al. 
Warr et al. 
Aprepitant (n = 261)
Standard (n = 264)
Aprepitant (n = 282)
Standard (n = 285)
Aprepitant (n = 438)
Standard (n = 428)
With ≥1 clinical adverse event
With drug-related* clinical adverse events
With serious clinical adverse events
Discontinued due to a clinical adverse event
With ≥1 laboratory adverse event
With drug-related laboratory adverse events
With most common clinical adverse events‡ Anorexia
Adverse events considered by the investigator to be possibly, probably or definitely related to study drug. ≥10% in at least one treatment group. There were no statistically significant (p > 0.1) risk differences between treatments for groupings of adverse events. NR: Not reported. Adapted from [48,47,51].
LaRusso, Waldman & Kraft
nausea and vomiting. Aprepitant is available as a Tripack, containing one 125-mg capsule and two 80-mg capsules. Aprepitant is also available as 40-mg capsules in the unit of one or five. Conclusion
Aprepitant represents a novel class of antiemetics (NK-1 antagonist) that offers a significant improvement in the prevention of CINV. When added to a 5-HT3 receptor antagonist and dexamethasone, aprepitant significantly improves the control of acute and delayed CINV for patients receiving highly emetogenic chemotherapy. Based on clinical studies, there is, however, a not significant improvement in the incidence of nausea. Aprepitant in a combination regimen should be considered as first-line antiemetic therapy in patients receiving highly emetogenic cisplatin chemotherapy. Aprepitant is also indicated for prevention of emesis associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. The use of aprepitant as part of a combination therapy is endorsed in American Society for Clinical Oncology  National Comprehensive Cancer Network (NCCN)  and Multinational Association of Supportive Care in Cancer  clinical guidelines. Moreover, the antiemetic utility has been extended to the prevention of PONV. The exact role of aprepitant relative to other agents has yet to be defined, due in part to the relative lack of a clear first choice among ‘classical’ prophylactic drugs for the PONV indication. Further studies are required to determine the efficacy of aprepitant in multiday chemotherapy, stem cell transplantation and in pediatric patients. As data in these fields become available, utilization of aprepitant may expand. Although aprepitant is well tolerated and associated with minimal adverse effects, clinicians should be aware of potential drug interactions. Patients on aprepitant therapy should be instructed to inform their oncologist if medications are added or discontinued while undergoing treatment. While currently an oral form is available, clinical utility will be expanded with fosaprepitant dimeglumine, an intravenous formulation under development . The addition of aprepitant is cost effective when utilized in populations at higher risk for delayed emesis . Maximal benefit is enjoyed by those patients at greatest risk based on chemotherapy exposure or clinical risk factors. Accordingly, the use of aprepitant for most patients at low risk for nausea and emesis is not endorsed. Expert commentary & five-year view
Aprepitant has provided significant insight into the relationship between substance P and emesis. As an agent with a novel target for the treatment of nausea and vomiting, aprepitant represents a substantial advance in therapy for these conditions in the field of chemotherapy and perioperative medicine. Particular advantages include excellent safety profile and additive efficacy with existing preventative agents.
Aprepitant-containing regimens appear to overcome the higher rates of emesis in female patients receiving chemotherapy . While the exact role of aprepitant for PONV relative to other agents remains to be established, the weight of evidence for benefit has resulted in the incorporation of this agent as part of a new standard-of-care regimen for prevention of CINV. The hierarchical role of aprepitant relative to other existing agents in the treatment of PONV will hopefully be established by further controlled clinical trials. It is likely that other NK-1 antagonists will enter the market. A number of agents have been investigated to various stages of development. These include netupitant (Helsin), befetupitant (Hoffmann-La Roche), vestipitant and casopitant (GlaxoSmithKline), lanepitant (Eli Lilly), ezlopitant (Pfizer), SCH-619734 (Schering-Plough) and dapitant (Sanofi). Of these, casopitant is presently in Phase III testing for an emesis indication [103,104]. Within the framework of nausea and emesis, future investigations with the use of aprepitant will likely extend to an intravenous formulation, pediatric use and potentially as a breakthrough treatment for established nausea and emesis. It is likely that aprepitant will be evaluated in combination with olanzapine and gabapentin, both of which are being investigated as agents for the prevention of CINV. The utility of aprepitant in other emetic conditions remains to be defined. The indications of migraine-associated emesis and chronic gastroparesis are areas that would benefit from expanded treatment options. Hyperemesis gravidum remains a challenging condition with a need for more evidence to support existing treatment approaches [57,58]. Aprepitant has a pregnancy grade of B; however, there are no reports of systematic testing in this population, making any firm recommendations on the use of aprepitant in pregnant patients difficult. An exploratory study has suggested that aprepitant may be effective in the treatment of postmenopausal urge incontinence . Other applications of NK-1 antagonism have not proven fruitful in clinical trials. An initially anticipated role in mood disorders was abandoned after aprepitant was demonstrated to be without efficacy as an antidepressant in a multicenter trial . A clinical trial of neuropathic pain using the NK-1 antagonist TKA-731 did not reveal therapeutic utility , nor did a trial of the NK-1 antagonist lanepitant in migraine headache prevention . Potential indications that continue to be investigated include tinnitus  and diarrhea associated with cryptosporidium . Despite the implication of NK in the pathophysiology of asthma, the dual NK-1 and NK-2 antagonist AVE-5883 did not influence inflammatory mediators in pretreated asthmatics exposed to NK . NK-2 and NK-3 antagonists have been evaluated in clinical trials for irritable bowel syndrome and schizophrenia, although none have been approved for clinical use. Given the breadth of the NK system, it is anticipated that clinical applications of this class of agents will continue to expand.
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Financial & competing interests disclosure
These activities were supported by grants from NIH (CA75123 and CA95026) and Targeted Diagnostic and Therapeutics, Inc. to SA Waldman. J LaRusso was enrolled in the NIH-supported institutional K30 Training Program in Human Investigation (K30 HL004522) and was supported by the NIH institutional award T32 GM08562 for Postdoctoral Training in Clinical Pharmacology. SA Waldman is the Samuel MV Hamilton Endowed Professor. SA Waldman and WK Kraft receive research support from Merck Research Laboratories. SA Waldman and WK Kraft are paid consultants to Merck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. References Papers of special note have been highlighted as: • of interest •• of considerable interest 1
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Intravenous And Oral Casopitant (GW679769) For The Prevention Of Chemotherapy Induced Nausea And Vomiting study http://clinicaltrials.gov/ct/show/NCT0036 6834;jsessionid=6274A63377DD8BDD3 BA09EEA03DD3514?order=32
A Study of the Drug Casopitant for the Prevention of Nausea Caused By CisplatinBased Highly Emetogenic Chemotherapy http://clinicaltrials.gov/ct2/show/NCT004 31236?intr=%22Oral+Casopitant+%28G W679769%29%22&cntry1=EU%3AIE& rank=1 Clintrials.gov
Vestipitant Or Vestipitant/Paroxetine Combination In Subjects With Tinnitus And Hearing Loss http://clinicaltrials.gov/ct2/show/NCT003 94056?term=vestipitant&rank=1 Clintrials.gov
Jennifer LaRusso, DO Thomas Jefferson University, Department of Pharmacology and Experimental Therapeutics, 132 South 10th Street, 1170 Main, Philadelphia, PA, USA Tel.: +1 215 955 4999 Fax: +1 215 955 5681 [email protected]
Scott A Waldman, MD, PhD Thomas Jefferson University, Department of Pharmacology and Experimental Therapeutics, 132 South 10th Street, 1170 Main, Philadelphia, PA, USA Tel.: +1 215 955 6086 Fax: +1 215 955 5681 [email protected]
Walter K Kraft, MD, MS Thomas Jefferson University, Department of Pharmacology and Experimental Therapeutics, 132 South 10th Street, 1170 Main, Philadelphia, PA, USA Tel.: +1 215 955 9077 Fax: +1 215 955 5681 [email protected]
NCCN Clinical Practice Guidelines in Oncology Antiemesis – version 1, www.nccn.org/professionals/physician_gls/ PDF/antiemesis.pdf Clinical guidelines for the prevention of CINV. Multinational Association Of Supportive Care In Cancer: Perugia International Cancer Conference VII: Consensus Committee on Antiemetic Therapy www.mascc.org/content/127.html Clinical guidelines for the prevention of CINV