Antiemetic Studies on the NK1 Receptor Antagonist Aprepitant

Home , Aprepitant, NK1 receptor antagonist

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Original Article

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 interaction 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 treatment 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

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 receptors 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

Aprepitant induces CYP2C9, but has no effect on CYP2D6. A - before cisplatin and 8 mg dexamethasone on days 2 to potential for drug interactions exists with 3A4 5. The three arms included a 375/250-mg group treated substrates, in particular, chemotherapy agents, dexa- with oral aprepitant 375 mg before cisplatin and 250 methasone and methylprednisolone (See subsequent mg on days 2 to 5; a 125/80-mg group treated with sections).25 Warfarin (Coumadin, Bristol-Myers Squibb oral aprepitant 125 mg before cisplatin and 80 mg on Company, Plainsboro, NJ) levels may be slightly re- days 2 to 5; and a standard therapy arm treated with duced because of the CYP2C9 effect, and international placebo before cisplatin and on days 2 to 5. normalized ratio (INR) monitoring is recommended for Although the study was ongoing, the 375/250-mg patients on warfarin. Aprepitant has no effect on the group was discontinued and replaced with a 40/25-mg concomitantly administered 5-HT3 RA, granisetron, group (40 mg aprepitant before cisplatin and 25 mg on and ondansetron (CYP2D6 substrates).24 days 2 to 5). This was done when new pharmacokinetic data from healthy volunteers revealed that the 375/250-mg doses resulted in plasma aprepitant levels Clinical Studies that were higher than expected and higher than nec- essary to block more than 90% of CNS NK1 receptor Early phase clinical trials of aprepitant or its intra- sites. The primary efficacy analysis focused on 381 pa- venous prodrug L-758,298 established the NK1 RA’s tients randomized according to the final trial design tolerability and safety, and suggested that combination and the primary study endpoint was complete response regimens of aprepitant, corticosteroids, and 5-HT3 RA (defined as no emesis and no use of rescue medication) have greater efficacy than single- or dual-agent regi- during the overall study period (days 1 to 5). Compared mens.26–29 In all studies, aprepitant was well tolerated. with standard therapy, complete responses were Common adverse events reported in 10% or more of treated patients in at least one treatment arm in these trials were abdominal pain, anorexia, asthenia, con- Table 1 Complete Response Data of Large stipation, dehydration, diarrhea, dizziness, headache, Randomized Studies of an Aprepitant and hiccups. In the three trials that included a treat- Regimen Versus Standard Therapy ment arm that did not receive a 5-HT3 RA (on- Complete Responsea dansetron or granisetron), diarrhea occurred Study Overall 0–24 h 2–5 d numerically more often compared with arms treated 30 with a 5-HT3 RA. No serious clinical adverse events Chawla et al. believed to be attributable to the study drug occurred, Control 44% 71% 45% and within each study, there were no significant dif- n = 126 ferences in laboratory measures of safety. Aprepitant 125/80 71%b 83%c 73%b n = 132 As clinical trials with aprepitant moved from early Aprepitant 40/25 59%c 76% 64%b stage clinical trials to phase III trials, corticosteroids n = 119 and a 5-HT3 RA prior to, and corticosteroids with or Poli-Bigelli et al.33 without 5HT3 RA or metoclopramide for 3 to 4 days Control 43% 68% 47% after highly emetogenic chemotherapy became stan- n = 263 dard preventative therapy. The results of three large Aprepitant 125/80 63%d 83%d 68%d randomized trials comparing the addition of aprepitant n = 260 to standard therapy to placebo plus standard therapy Hesketh et al.32 have been completed.30–33 In all three trials standard Control 52% 78% 56% therapy included corticosteroid and 5-HT3 RA on N = 260 day 1 and corticosteroids on days 2 to 4 or 5. Aprepitant 125/80 73%d 89%d 75%d Chawla et al.30 reported the results of a large dose- n = 260 finding study. This was designed as a three-arm trial, and two dose schedules of aprepitant containing com- aDefined as complete absence of vomiting and no use of bination therapy were compared with standard ther- rescue medicines. bP < .01 vs. standard therapy. apy. All patients were treated with 32 mg intravenous cP < .05 vs. standard therapy. ondansetron and 20 mg intravenous dexamethasone dP < .001 vs. standard therapy.

Stoutenburg and Raftopoulos

significantly greater in each aprepitant group during the amethasone 12 mg on day 1, oral aprepitant 80 mg overall study period and during the delayed phase and oral dexamethasone 8 mg once daily on days 2 (Table 1). For the secondary endpoints of no emesis, and 3, and oral dexamethasone 8 mg on day 4. no nausea, total control, and complete protection, both The Apreptant Protocol 054 Study was largely aprepitant-containing groups were significantly more conducted in Latin America. In this study, 569 pa- effective than standard therapy during the overall study tients were randomized to receive one of the two treat- period. When the data were analyzed by phase (acute ment groups specified previously.33 As in the Chawla and delayed), the 125/80-mg group was statistically et al. study, the complete response rate during the more effective for the endpoints of complete response, overall study period was the primary endpoint (Table complete protection, and no emesis during the acute 1). The study showed that 62.7% of the apreptitant- phase. During the delayed phase, the 125/80-mg group treated patients, as compared with 43.4% of the con- was statistically superior to standard therapy by all study trol group, showed a complete response (P < .001). endpoints. Compared with standard therapy, the 40/ When analyzed by time intervals, complete responses 25-mg group was not statistically superior for any end- were greater in the both the acute (82.8% vs. 68.4%; point during the acute phase, but showed significantly P < .001) and delayed-phases (67.7% vs. 46.8%; P < improved control during the delayed phase, with nu- .001). merical superiority by all study endpoints and signifi- For the secondary endpoints, the aprepitant arm cant benefit for complete response, no emesis, no had a significantly greater number of patients with no rescue, no vomiting, complete protection, and total nausea in both the delayed phase and the overall study control. The overall incidence of adverse events was period. Additionally, a significantly greater number similar across all treatments groups. However, a higher of patients with complete protection (no emesis, no incidence of infection was seen in the 125/80-mg group rescue medication, and no significant nausea) at all than in the standard therapy group (13% vs. 4%). time points were noted in the aprepitant arm. No dif- Researchers hypothesized that this was caused by a ferences were seen in the toxicity profiles of each arm pharmacokinetic interaction of aprepitant that resulted in terms of clinical adverse events, drug-related clin- in greater exposure to dexamethasone. No drug inter- ical adverse events, serious clinical adverse events, actions were reported. Overall, the trial showed that laboratory adverse events, drug-related laboratory ad- (1) the addition of aprepitant to standard therapy im- verse events, and discontinuations. The steroid doses proved control of CINV and (2) the125/80-mg doses used in this study were lower than those in the Chawla provided greater protection than the 40/25-mg dose. et al. study, and no increase in infectious complications Based on efficacy and tolerability, the aprepitant was noted. A possible drug interaction was reported in 125/80-mg dose was chosen as the appropriate regi- patients who received concomitant treatment with a men for further studies. CYP3A4 metabolism-dependent chemotherapeutic Two large, randomized, phase III, double-blind, agent (etoposide, vinorelbine, and taxanes): in this placebo-controlled studies (052 and 054 studies) were subgroup, the incidence of serious adverse events was initiated with similar entry criteria and dosing regi- greater in the aprepitant arm compared with standard mens.32,33 They both evaluated the addition of aprepi- therapy (15.8% vs. 8.5%). In contrast, the incidence tant to standard therapy during administration of an was lower in the aprepitant treated arm for patients initial cycle of a cisplatin (dose, 70 mg/m2 or greater)- who did not receive concurrent CYP3A4 metabolized containing chemotherapy regimen. The antiemetic chemotherapy (4.2% vs. 11.6%). dosing regimen was modified to account for the The third large study to evaluate the addition of CYP3A4 interaction between aprepitant and dexam- aprepitant to standard therapy was reported by the ethasone and approximate equivalent dexamethasone Aprepitant 052 Study Group.32 In this multinational exposure in both arms. Patients in the control group phase III study, 530 patients were randomized to the received intravenous ondansetron 32 mg and oral dexa- same treatment groups as in the 054 Study. Again, methasone 20 mg on day 1, followed by oral dexa- findings showed statistically significant benefits fa- methasone 8 mg twice daily on days 2 to 4. Patients voring the aprepitant arm in terms of complete re- in the aprepitant group received oral aprepitant 125 sponses for the overall study period (72.7% vs 52.3%; mg plus intravenous ondansetron 32 mg and oral dex- P < .001), the acute (89.2% vs. 78.1%; P < .001), and

Aprepitant the delayed-phases (75.4% vs 55.8%; P < .001; Table efficacy of these two treatment groups is concordant 1). Secondary endpoint data showed significantly with results from a positron-emission tomography im- greater responses in the aprepitant arm at all time aging study that showed L-758,298 doses of 300-mg points for the endpoints of no emesis, no rescue, and and 125 mg were equally effective in blocking 90% or 35 complete protection. The toxicity profiles of each arm more of CNS NK1 receptors. were similar, and the common clinical adverse events No statistically significant differences in adverse reported in at least 10% in one treatment arm were as- events were reported between the treatment arms. thenia-fatigue, constipation, hiccups, and nausea oc- However, numerically, more serious adverse events curring after day 5. In contrast to the 054 Study, no occurred over cycles 2 to 6 in the 125/80-mg group. increased incidence of serious adverse events in pa- These were not reported as attributable to the study tients treated with concomitant CYP3A4 metabolized drug. The increase is accounted for by a greater num- chemotherapeutic agents was reported in the 052 ber of febrile neutropenic and infection-related ad- Study. In summary, all three large, randomized, verse events in the aprepitant group. Again, this is placebo-controlled, trials demonstrated significant im- thought to be caused by a pharmacokinetic interaction provement in control of CINV with the addition of of aprepitant that results in increased corticosteroid aprepitant to standard therapy. levels. The steroid dose used in the delayed-phase was A combined analysis of the 052 and 054 studies lower in studies 052 and 054 than in the de Wit et al. showed that, in addition to the superiority of the or Chawla et al. studies, and no increased rates of se- aprepitant regimen, with the addition of aprepitant rious adverse events, febrile neutropenia, or infection- to standard therapy, no gender difference was seen in related adverse events were found. complete response rates after highly emetogenic De Wit et al.36 published a second, similar exten- chemotherapy.34 Results showed that 86% of women sion study that combined patients enrolled in Studies versus 87% of men achieved a complete response with 052 and 054. The study’s primary endpoint, a com- aprepitant; however, only 66% of women and 80% of bined exploratory endpoint of no emesis and no sig- men achieved a complete response in the control nificant nausea, was evaluated for up to 6 cycles of group. cisplatin-based chemotherapy. Using a cumulative Studies 052, 054, and the Chawla et al. study all probabilities approach, the estimated probability rates evaluated the efficacy of aprepitant as part of combi- of no emesis and no significant nausea were signifi- nation antiemetic therapy during the initial cycle of cantly greater across all cycles for the aprepitant- cisplatin containing chemotherapy in cisplatin-naïve treated patients compared with patients receiving patients. In an extension phase of the Chawla et al. standard therapy (61% vs. 46%; P < .001; 59% vs. study, de Wit et al.31 reported on the efficacy of aprepi- 40%; P < .001, for cycles 1 and 6, respectively). The tant-containing combination therapy over multiple toxicity profiles of the treatment groups were compa- cycles (up to 6) of cisplatin-containing chemother- rable and no cumulative toxicities attributable to apy. The 202 patients randomized by the initial trial aprepitant were identified. This second study con- design were reported on in the extension phase of the firmed the improved antiemetic control with contin- study. Comparing the125/80-mg group and the stan- ued aprepitant use during multiple cycles of highly dard arm, complete responses during cycle 1 were emetogenic chemotherapy. achieved in 64% and 49%, respectively (P < .05). The Functional Living Index-Emesis (FLIE) ques- During cycles 5 and 6, the complete response rate re- tionnaire was administered in the 052, 054, and mained statistically greater for the 125/80-mg arm Chawla et al. studies to evaluate the impact of CINV (59% vs. 34%; P < .05). Although the efficacy of the on patients’ daily lives.32,33,37 This is a validated nausea 125/80-mg group was maintained from cycle 1 to 6 and vomiting-specific patient-reported outcome mea- (complete responses of 64% and 59%), the response sure. The FLIE results were significantly better for rate of standard therapy decreased by 15% between aprepitant groups compared with standard therapy in cycles 1 and 6 (49% and 34%). No formal comparisons all studies (Table 2). In the 054 study, 74.7% and were made for the 375/250-mg group, but complete re- 63.5% of aprepitant versus standard therapy patients sponses rates during cycles 1 and 6 were similar to had scores consistent with “minimal or no impact of those of the 125/80-mg group. The finding of similar CINV on daily life.”

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Table 2 Observed Percent of Patients With with moderately emetogenic therapy are now com- “Minimal or No Impact on Daily Life” plete and currently being analyzed. or “No Impact on Daily Life” by Treatment Group as Measured by References FLIE Questionnaire 1. Jantunen IT, Kataja VV, Muhonen TT: An overview of ran- Aprepitant Standard domised studies comparing 5-HT3 receptor antagonists to Study Group Therapy Group conventional anti-emetics in the prophylaxis of acute Poli-Bigelli et al.33 74.7%a 63.5% chemotherapy-induced vomiting. Eur J Cancer 1997;33: 66–74. Hesketh et al.32 74.0%a 64.3% 2. Grunberg SM, Hansen M, Deuson R, et al: Incidence and im- 37 b Martin et al. 84% 66% pact of nausea/vomiting with modern antiemetics: perception vs. reality. Cancer 2004;100:2261–2268. a P value not stated. Endpoint reported was percentage of 3. Roila F, Donati D, Tamberi S, et al: Delayed emesis: inci- patients with “minimal or no impact on daily life.” dence, pattern, prognostic factors and optimal treatment. bP < 0.01. Endpoint reported was percentage of patients with “no impact on daily life.” Value reported is for Support Care Cancer 2002;10:88–95. 125/80-mg group. 4. ASHP Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or The 052 Study results for the same outcome mea- Undergoing Surgery. Am J Health Syst Pharm 1999;56: sure were 74.0% and 64.3% for the aprepitant and 729–764. standard therapy arms, respectively. The FLIE results 5. ESMO Recommendations for prophylaxis of chemotherapy- induced nausea and vomiting (NV). Ann Oncol 2001;12: from the Chawla et al. study were reported separately, 1059–1060. and for the primary endpoint of “no impact on daily 6. Fauser AA, Fellhauer M, Hoffmann M, et al: Guidelines for life” the results again favored the aprepitant (125/ anti-emetic therapy: acute emesis. Eur J Cancer 1999;35: 80-mg) group (84% vs. 66%; P < .01).37 Together, the 361–370. FLIE data from these studies suggest an absolute in- 7. Gralla RJ, Osoba D, Kris MG, et al: Recommendations for crease of at least 10% in the number of patients who the use of antiemetics: evidence-based, clinical practice guide- have “minimal or no impact of CINV on daily life” as- lines. American Society of Clinical Oncology. J Clin Oncol sociated with the addition of aprepitant to standard 1999;17:2971–2994. therapy for cancer patients treated with highly eme- 8. Koeller JM, Aapro MS, Gralla RJ, et al: Antiemetic guidelines: creating a more practical treatment approach. Support togenic chemotherapy. Care Cancer 2002;10:519–522. 9. NCCN antiemesis practice guidelines. Oncology Conclusions 1997;11(suppl):57–89. Update available at: http://www. The addition of aprepitant to corticosteroids and nccn.org. Accessed July 2004. 5-HT3 RA as prevention for CINV has been shown 10. Roila F: Transferring scientific evidence to oncological prac- repeatedly to provide significantly improved control tice: A trial on the impact of three different implementation strategies on antiemetic prescriptions. Support Care Cancer, for cancer patients treated with cisplatin-based ther- 2004;12:446453. apy. With triple-agent combination therapy, more pa- 11. Schnell FM: Chemotherapy-induced nausea and vomiting: tients are able to complete treatment with minimal The importance of acute antiemetic control. Oncologist impact on daily life. The therapy is generally well tol- 2003;8:187–198. erated and the common side effects are similar to those 12. Grunberg SM, Hesketh PJ: Control of chemotherapy- of standard therapy; the common adverse events en- induced emesis. N Engl J Med 1993;329:1790–1796. countered include anorexia, asthenia-fatigue, consti- 13. Andrews PL, Davis CJ, Bingham S, et al: The abdominal vis- pation, diarrhea, hiccups, and nausea after day 5. The ceral innervation and the emetic reflex: pathways, pharma- question of a possible drug interaction with CYP3A4 cology, and plasticity. Can J Physiol Pharmacol 1990;68: 325–345. metabolized chemotherapeutic agents remains and 14. Saria A: The tachykinin NK1 receptor in the brain: phar- continues to be evaluated. The use of aprepitant should macology and putative functions. Eur J Pharmacol be considered in all cancer patients undergoing treat- 1999;375:51–60. ment with highly emetogenic chemotherapy. Studies 15. Otsuka M, Yoshioka K: Neurotransmitter functions of mam- to evaluate whether these benefits are also realized malian tachykinins. Physiol Rev 1993;73:229–308.

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