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Antiemetic Studies on the NK1 Receptor Antagonist Aprepitant

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Antiemetic Studies on the NK1 Receptor Antagonist Aprepitant 491 Original Article Antiemetic Studies on the NK1 Receptor Antagonist Aprepitant John P. Stoutenburg, MD, and Harry Raftopoulos, MD, New York, New York Key Words protection to standard therapy and should be considered in all Aprepitant, antiemetics, chemotherapy, substance P patients receiving highly emetogenic chemotherapy. (JNCCN 2004;2:491–497) ABSTRACT Aprepitant (Emend, Merck Inc., Whitehouse Station, NJ), a neurokin-1 In the past 15 years, significant advances have been (NK1) receptor antagonist, is a first-in-class agent approved for the made in the prevention of chemotherapy-induced nau- prevention of acute and delayed chemotherapy-induced nausea sea and vomiting (CINV). Despite these advances, the and vomiting (CINV). It competitively binds to NK1 receptors, blocks ultimate goal of antiemetic therapy—to completely pre- the binding of substance P, the natural ligand, and prevents signal transduction. Early clinical trials showed that aprepitant combined vent nausea and vomiting in all settings—remains elu- 1 with standard therapy (corticosteroids and serotonin receptor an- sive. Considerable numbers of patients continue to tagonists) provided improved antiemetic protection in patients re- experience CINV, and recent evidence indicates health ceiving highly emetogenic chemotherapy. The results of three care professionals substantially underestimate the inci- randomized, double blind, placebo-controlled trials that compared dence of CINV and overestimate the degree of control.2 aprepitant plus standard therapy with standard therapy plus placebo showed significant improvements in complete response rates (de- The antiemetics most effective in preventing CINV, fined as no emesis and no use of rescue medication) with the addi- serotonin (type 3 5-hydroxytryptamine) receptor an- tion of aprepitant (58.8% to 71% vs. 43.3% to 52.3%; P < .05 for all). tagonists (5-HT3 RA), corticosteroids, and dopamine Benefits were found in the acute phases, delayed phases, and in the receptor antagonists (metoclopramide), are used alone overall study periods. Multiple secondary endpoints also favored and in combination to prevent acute (occurring in the the addition of aprepitant, particularly in the delayed phases and first 24 hours after chemotherapy administration) and overall study periods. In extended trials in which treatment was con- tinued for up to 6 cycles of highly emetogenic chemotherapy, the delayed (occurring days 2 to 5 after chemotherapy ad- 3 antiemetic effect was maintained and remained statistically greater ministration) CINV. Multiple organizations have pub- for the aprepitant plus standard therapy group compared with stan- lished evidence-based practice guidelines to facilitate dard therapy and placebo. The addition of aprepitant was well tol- the incorporation of these agents into clinical prac- erated, and common adverse events were similar to those seen with tice.4–9 Although these guidelines largely incorporate standard therapy plus placebo. A clinically significant drug interac- tion with CYP3A4-metabolized cytotoxic agents was reported in high level I recommendations to minimize CINV, ad- 10 one trial, but not confirmed in the others. The additional protection herence to these guidelines is not uniform. Despite an confirmed by aprepitant translated into a decreased impact of CINV improved understanding of how to effectively use these on patients’ daily lives as measured by the Functional Living Index- agents, many patients still suffer distressing side effects. Emesis questionnaire. Aprepitant adds additional antiemetic Not only are these symptoms physically and psycho- logically uncomfortable, they are associated with treat- ment delays, discontinuations, and greater financial From Columbia University Medical Center, New York, New York. costs.11 Better control of CINV can be achieved by both Submitted May 17, 2004; accepted for publication July 12, 2004. enhancing adherence to guidelines and by exploring Dr. Stoutenburg has no financial conflicts of interest to report. Dr. Raftopoulos received more than $2,000 from Merck in 2003 for drugs with new mechanisms of action. Improved un- speaking fees. derstanding of the pathophysiologic mechanisms of Correspondence: Harry Raftopoulos, MD, 161 Fort Washington Avenue, HIP 9-909, New York, NY 10032. E-mail: CINV has resulted in the development of a new class of [email protected] antiemetics, the neurokin-1 receptor antagonists (NK1 © Journal of the National Comprehensive Cancer Network | Volume 2 Number 5 | September 2004 492 Original Article Stoutenburg and Raftopoulos RA). Aprepitant (Emend, L-754,030, MK-0869; mice exhibit minimal, if any, abnormalities, and are Merck and Co Inc, Whitehouse Station, NJ) is the developmentally normal and fertile.17 Different classes first drug in this class to receive Food and Drug of antiemetics are effective against different mecha- Administration (FDA) approval and with an indi- nisms of CINV and, when used in combination, are cation, in conjunction with other antiemetics, for more effective in preventing CINV caused by highly preventing both acute and delayed CINV. The pur- emetogenic chemotherapy than when used alone. pose of this article is to review the clinical experience 5-HT3 RA (dolasetron, granisetron, ondansetron, and with aprepitant in the prevention of CINV for tropisetron) now play an integral role in the preven- patients receiving highly emetogenic chemotherapy. tion of acute CINV. These agents block 5-HT recep- tors on the abdominal afferent vagal nerves, preventing depolarization and further stimulation of the vomit- Pathophysiology of CINV ing center within the brainstem.12 Metoclopramide, an agent effective in both acute and delayed CINV, Although comprehension of the pathophysiologic antagonizes centrally-located dopamine receptors mechanisms of CINV has improved, overall knowledge and at high doses inhibits 5-HT3 receptors.18 is limited. Cytoxic agents induce nausea and vomit- Corticosteroids, through unclear mechanisms of ac- ing through multiple mechanisms, and these differ by tion, possibly anti-inflammatory effects, are also ef- agent. Agents may induce symptoms through periph- fective in both acute and delayed CINV. Despite eral, central, or a combination of peripheral and cen- combinations of these agents, a substantial portion of tral pathways.12 The mechanisms involved in patients (30% to 50%) receiving highly emetogenic acute-phase CINV are believed to be different from chemotherapy still experience nausea and vomiting, those involved in delayed-phase CINV. Different particularly during the delayed-phase.6 In addition to mechanisms result in activation of the chemorecep- the inherent emetogenicity of a particular chemother- tor trigger zone (CTZ) located in the area postrema of apeutic agent, other modifying risk factors for the de- the brainstem. Once it is activated, neurotransmit- velopment of CINV are recognized. These include ters are released from the CTZ and stimulate the vom- major factors such as young age, female gender, and low iting center. Dopamine, serotonin (5-HT), and alcohol consumption. Minor factors are a history of substance P (SP) are neurotransmitters that have been motion sickness or emesis with pregnancy.19 extensively studied in connection with CINV.12 5-HT is an important neurotransmitter in a well-described peripheral pathway. Highly emetogenic cytotoxic agents induce the release of 5-HT from enterochro- Preclinical Studies and Pharmacology maffin cells located in the gastrointestinal tract. The The induction of emesis in ferrets through cisplatin ad- released 5-HT acts on adjacent abdominal afferent ministration is a model for CINV that was validated vagal nerves, induces depolarization and stimulation in the development of 5-HT3 RA and similarly used 13 20–23 of the vomiting center in the brainstem. in the investigation of NK1 RA. Intravenous aprepi- The role of SP is a more recently described find- tant prodrug and oral aprepitant significantly inhibit ing. A peptide of the neurokinin family, SP is found acute retching and vomiting in ferrets exposed to cis- in vagal afferent nerves within the gastrointestinal platin.22 In an evaluation of the protective effects in tract and in regions of the central nervous system acute and delayed-phases of CINV, aprepitant ad- (CNS) involved in control of the vomiting reflex (the ministered before cisplatin completely prevented acute nucleus tractus solitarius and area postrema).14 The retching and vomiting. When administered after cis- biologic effects of SP are mediated through a platin-induced emesis was already established, aprepi- 21 tachykinin receptor, NK1, a G-protein receptor cou- titant prevented further retching and vomiting. With pled to the inositol phosphate signal-transduction the efficacy of aprepitant established in the ferret pathway.15 A study finding that local administration model, pharmacokinetic studies and clinical trials were of SP-induced vomiting in ferrets and that NK1 RA can pursued. inhibit this action supported the role of SP in the reg- Aprepitant is extensively metabolized in the liver 16 ulation of emesis. The basic function of the NK1 re- and is both a substrate and a moderate inhibitor of the 24 ceptor is still not well-defined; NK1 receptor knock-out cytochrome (CYP) P450 3A4 system. In addition, it © Journal of the National Comprehensive Cancer Network | Volume 2 Number 5 | September 2004 Original Article 493 Aprepitant induces CYP2C9, but has no effect on CYP2D6. A - before cisplatin and 8 mg
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