Skip to main content
SpringerLink
Log in
Book cover

Management of Chemotherapy-Induced Nausea and Vomiting pp 85–105Cite as

The Role of Neurokinin-1 Receptor Antagonists in CINV

  • Chapter
  • First Online:

  • 1060 Accesses

Abstract

Significant advances have been made in controlling chemotherapy-induced nausea and vomiting (CINV) in the past two decades. These advances are primarily due to a greater understanding of the physiological and molecular pathways underlying CINV, which resulted in major progress in the management of patients with CINV. In the early 1990s, CINV treatment included dexamethasone [1]. Improvements in the management of CINV control were achieved with the discovery of 5-hydroxytryptamine (5HT3) receptor and the development of 5HT3 receptor antagonists (RA). Additional improvements in CINV control were further made, with the usage of the combination of 5HT3 RA with dexamethasone or other corticosteroid agents at equivalent doses [2, 3].

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   54.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Aapro MS, Alberts DS (1981) Dexamethasone as an antiemetic in patients treated with cisplatin. N Engl J Med 305(9):520

    CAS  PubMed  Google Scholar 

  2. Falkson G, van Zyl AJ (1989) A phase I study of a new 5HT3-receptor antagonist, BRL43694A, an agent for the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol 24(3):193–196

    Article  CAS  PubMed  Google Scholar 

  3. Smith DB, Newlands ES, Spruyt OW, Begent RH, Rustin GJ, Mellor B, Bagshawe KD (1990) Ondansetron (GR38032F) plus dexamethasone: effective anti-emetic prophylaxis for patients receiving cytotoxic chemotherapy. Br J Cancer 61(2):323–324

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Hesketh PJ, Grunberg SM, Gralla RJ et al (2003) The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the aprepitant protocol 052 study group. J Clin Oncol 21:4112–4119

    Article  CAS  PubMed  Google Scholar 

  5. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD et al (2003) Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 97:3090–3098

    Article  CAS  PubMed  Google Scholar 

  6. Warr DG, Hesketh PJ, Gralla RJ et al (2005) Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 23:2822–2830

    Article  CAS  PubMed  Google Scholar 

  7. Rapoport BL, Jordan K, Boice JA, et al (2010) Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Cancer 18(14):428–431

    Google Scholar 

  8. National Comprehensive Cancer Network. NCNN Guidelines 1.2012: Antiemesis 1.2012. 2012. Report No.: 1.2012

    Google Scholar 

  9. Roila F, Herrstedt J, Aapro M et al (2010) Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 21(Suppl 5):v232–v243

    Article  PubMed  Google Scholar 

  10. Hesketh PJ, Bohlke K, Lyman GH, Basch E, Chesney M, Clark-Snow RA, Danso MA, Jordan K, Somerfield MR, Kris MG. Antiemetics: American Society of Clinical Oncology Focused Guideline Update. J Clin Oncol. 2015 Nov 2. pii: JCO.2015.64.3635. [Epub ahead of print]

    Google Scholar 

  11. Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J (2011) Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol 29(11):1495–1501

    Article  CAS  PubMed  Google Scholar 

  12. Arpornwirat W, Albert I, Hansen VL et al (2009) Phase 2 trial results with the novel neurokinin-1 receptor antagonist casopitant in combination with ondansetron and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting in cancer patients receiving moderately emetogenic chemotherapy. Cancer 115(24):5807–5816

    Article  CAS  PubMed  Google Scholar 

  13. Roila F, Rolski J, Ramlau R et al (2009) Randomized, double-blind, dose-ranging trial of the oral neurokinin-1 receptor antagonist casopitant mesylate for the prevention of cisplatin-induced nausea and vomiting. Ann Oncol 20(11):1867–1873

    Article  CAS  PubMed  Google Scholar 

  14. Grunberg SM, Rolski J, Strausz J et al (2009) Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled trial. Lancet Oncol 10:549–558

    Article  CAS  PubMed  Google Scholar 

  15. Stathis M, Pietra C, Rojas C, Slusher BS (2012) Inhibition of substance P-mediated responses in NG108-15 cells by netupitant and palonosetron exhibit synergistic effects. Eur J Pharmacol 689(1-3):25–30

    Article  CAS  PubMed  Google Scholar 

  16. Duffy RA, Morgan C, Naylor R, Higgins GA, Varty GB, Lachowicz JE, Parker EM (2012) Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets. Pharmacol Biochem Behav 102(1):95–100

    Article  CAS  PubMed  Google Scholar 

  17. Calcagnile S, Lanzarotti C, Rossi G, Henriksson A, Kammerer KP, Timmer W (2013) Effect of netupitant, a highly selective NK1 receptor antagonist, on the pharmacokinetics of palonosetron and impact of the fixed dose combination of netupitant and palonosetron when coadministered with ketoconazole, rifampicin, and oral contraceptives. Support Care Cancer 21(10):2879–2887

    Article  PubMed  Google Scholar 

  18. Gan TJ, Gu J, Singla N, Chung F, Pearman MH, Bergese SD, Habib AS, Candiotti KA, Mo Y, Huyck S, Creed MR, Cantillon M, Rolapitant Investigation Group (2011) Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial. Anesth Analg 112(4):804–812

    Article  CAS  PubMed  Google Scholar 

  19. Poma A, Christensen J, Davis J, Kansra V, Martell RE, Hedley ML. Phase 1 positron emission tomography (PET) study of the receptor occupancy of rolapitant, a novel NK-1 receptor antagonist.J Clin Oncol 2014; 32(suppl):abstr e20690

    Google Scholar 

  20. Poma A, Christensen J, Pentikis H et al (2013) Rolapitant and its major metabolite do not affect the pharmacokinetics of midazolam, a sensitive cytochrome P450 3A4 Substrate. Abstract 0441, MASCC/ISOO Symposium 2013. Support Care Cancer 21(1 Suppl)

    Google Scholar 

  21. Tavorath R, Hesketh PJ (1996) Drug treatment of chemotherapy-induced delayed emesis. Drugs 52:639–648

    Article  CAS  PubMed  Google Scholar 

  22. Wilder-Smith OH, Borgeat A, Chappuis P et al (1993) Urinary serotonin metabolite excretion during cisplatin chemotherapy. Cancer 72:2239–2241

    Article  CAS  PubMed  Google Scholar 

  23. Hesketh PJ, Warr DG, Street JC et al (2011) Differential time course of action of 5-HT3 and NK1 receptor antagonists when used with highly and moderately emetogenic chemotherapy (HEC and MEC). Support Care Cancer 19(9):1297–1302

    Article  PubMed  Google Scholar 

  24. Mantovani G, Maccio A, Curreli L et al (1998) Comparison of oral 5-HT3-receptor antagonists and low-dose oral metoclopramide plus I.M. dexamethasone for the prevention of delayed emesis in head and neck cancer patients receiving high-dose cisplatin. Oncol Rep 5:273–280

    CAS  PubMed  Google Scholar 

  25. Warr DG, Grunberg SM, Gralla RJ et al (2005) The oral NK(1) antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: pooled data from 2 randomised, double-blind, placebo controlled trials. Eur J Cancer 41:1278–1285

    Article  CAS  PubMed  Google Scholar 

  26. Martin M (1996) The severity and pattern of emesis following different cytotoxic agents. Oncology 53(Suppl 1):26–31

    Article  PubMed  Google Scholar 

  27. Lasseter KC, Gambale J, Jin B et al (2007) Tolerability of fosaprepitant and bioequivalency to aprepitant in healthy subjects. J Clin Pharmacol 47:834–840

    Article  CAS  PubMed  Google Scholar 

  28. Hesketh PJ, Rossi G, Rizzi G, Palmas M, Alyasova A, Bondarenko I, Lisyanskaya A, Gralla RJ (2014) Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol 25(7):1340–1346

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Rapoport BL, Poma A, Hedley ML et al (2014) Phase 3 trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving highly emetogenic chemotherapy (HEC). J Clin Oncol 32:32

    Google Scholar 

  30. Aapro M, Karthaus M, Schwartzberg LS et al (2014) Phase 3 study of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting during repeated moderately emetogenic chemotherapy cycles [abstract]. J Clin Oncol 32(Suppl 5):9502

    Google Scholar 

  31. Schmoll HJ, Aapro MS, Poli-Bigelli S, Kim HK, Park K, Jordan K, von Pawel J, Giezek H, Ahmed T, Chan CY (2006) Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol 17(6):1000–1006

    Article  CAS  PubMed  Google Scholar 

  32. Herrington JD, Jaskiewicz AD, Song J (2008) Randomized, placebo-controlled, pilot study evaluating aprepitant single dose plus palonosetron and dexamethasone for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. Cancer 112:2080–2087.24

    Article  CAS  PubMed  Google Scholar 

  33. Grunberg SM, Dugan M, Muss H et al (2009) Effectiveness of a single-day three-drug regimen of dexamethasone, palonosetron, and aprepitant for the prevention of acute and delayed nausea and vomiting caused by moderately emetogenic chemotherapy. Support Care Cancer 17:589–594

    Article  PubMed  Google Scholar 

  34. Van Belle SJ, Cocquyt V (2008) Fosaprepitant dimeglumine (MK-0517 or L-785,298), an intravenous neurokinin-1 antagonist for the prevention of chemotherapy induced nausea and vomiting. Expert Opin Pharmacother 9(18):3261–3270

    Article  PubMed  Google Scholar 

  35. Saito H, Yoshizawa H, Yoshimori K, Katakami N, Katsumata N, Kawahara M, Eguchi K (2013) Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Ann Oncol 24(4):1067–1073

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. de Wit R, Herrstedt J, Rapoport B, Carides AD, Guoguang-Ma J, Elmer M, Schmidt C, Evans JK, Horgan KJ (2004) The oral NK(1) antagonist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy: a combined analysis of two randomised, placebo-controlled phase III clinical trials. Eur J Cancer 40(3):403–410

    Article  PubMed  Google Scholar 

  37. de Wit R, Herrstedt J, Rapoport B, Carides AD, Carides G, Elmer M, Schmidt C, Evans JK, Horgan KJ (2003) Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy. J Clin Oncol 21(22):4105–4111

    Article  PubMed  Google Scholar 

  38. Rapoport B, Chua D, Poma A, Arora S, Wang Y, Fein LE (2015) Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). Support Care Cancer 23(11):3281–3288

    Google Scholar 

  39. Rapoport BL, Poma A, Hedley ML, Martel RE, Navari RM (2014) Phase III trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving highly emetogenic chemotherapy (HEC) [abstract] J Clin Oncol 32(Suppl 5):9638. Rapoport B, Chasen M, Gridelli M, Urban L, Modiano M, Schnadig I, Poma A, Arora S, Kansra V, Schwartzberg L, Navari R Safety and efficacy assessment of rolapitant for the prevention of chemotherapy‐induced nausea and vomiting following administration of cisplatin-based highly emetogenic chemotherapy in cancer patients in two randomised Phase 3 Trials. Lancet Oncol (Manuscript in press)

    Google Scholar 

  40. Schnadig ID, Modiano MR, Poma A, Hedley ML, Martel RE, Schwartzberg LS (2014) Phase III trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (MEC) [abstract] J Clin Oncol 32(Suppl 5):9633. Schwartzberg L, Modiano M, Rapoport B, Chasen M, Gridelli B, Urban L, Poma A, Arora S, Navari R, Schnadig I Safety and efficacy assessment of rolapitant for the prevention of chemotherapy-induced nausea and vomiting following administration of moderately emetogenic chemotherapy in cancer patients in a randomised phase 3 trial. Lancet Oncol (Manuscript in press)

    Google Scholar 

  41. Rojas C, Thomas AG, Alt J et al (2010) Palonosetron triggers 5-HT3 receptor internalization and causes prolonged inhibition of receptor function. Eur J Pharmacol 626:193–199

    Article  CAS  PubMed  Google Scholar 

  42. Rojas C, Slusher BS (2012) Pharmacological mechanisms of 5-HT3 tachykinin NK-1 receptor antagonism to prevent chemotherapy-induced nausea and vomiting. Eur J Pharmacol 684:1–7

    Article  CAS  PubMed  Google Scholar 

  43. Aapro M, Rugo H, Rossi G et al (2014) A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 25:1328–1333

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Schwartzberg L, Aapro M, Hesketh PJ et al (2014) do NK-1 receptor antagonists contribute to nausea control. Evaluation of the novel NEPA fixed-dose combination of NK-1 receptor antagonist plus a 5-HT3 receptor antagonist from pivotal trials. Support Care Cancer 22:S107, Abstract 161

    Google Scholar 

  45. US Food and Drug Administration (2014) FDA approves Akynzeo for nausea and vomiting associated with cancer chemotherapy [press release]. US Food and Drug Administration, Silver Springs, Accessed 30 Apr 2015. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements

    Google Scholar 

  46. Stiff PJ, Fox-Geiman MP, Kiley K et al (2013) Prevention of nausea and vomiting associated with stem cell transplant: results of a prospective, randomized trial of aprepitant used with highly emetogenic preparative regimens. Biol Blood Marrow Transplant 19(1):49–55

    Article  CAS  PubMed  Google Scholar 

  47. Pielichowski W, Barzal J, Gawronski K et al (2011) A triple-drug combination to prevent nausea and vomiting following BEAM chemotherapy before autologous hematopoietic stem cell transplantation. Transplant Proc 43(8):3107–3110

    Article  CAS  PubMed  Google Scholar 

  48. Badar T, Cortes J, Borthakur G, O'Brien S, Wierda W, Garcia-Manero G, Ferrajoli A, Kadia T, Poku R, Kantarjian H, Mattiuzzi G (2015) Phase II, open label, randomized comparative trial of ondansetron alone versus the combination of ondansetron and aprepitant for the prevention of nausea and vomiting in patients with hematologic malignancies receiving regimens containing high-dose cytarabine. Biomed Res Int 2015:497597

    Article  PubMed Central  PubMed  Google Scholar 

  49. Egerer G, Eisenlohr K, Gronkowski M, Burhenne J, Riedel KD, Mikus G (2010) The NK(1) receptor antagonist aprepitant does not alter the pharmacokinetics of high-dose melphalan chemotherapy in patients with multiple myeloma. Br J Clin Pharmacol 70(6):903–907

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Schmitt T, Goldschmidt H, Neben K, Freiberger A, Hüsing J, Gronkowski M, Thalheimer M, le Pelzl H, Mikus G, Burhenne J, Ho AD, Egerer G (2014) Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: results of a randomized, placebo-controlled phase III trial. J Clin Oncol 32(30):3413–3420

    Article  CAS  PubMed  Google Scholar 

  51. Bechtel T, McBride A, Crawford B, Bullington S, Hofmeister CC, Benson DM Jr, Jaglowski S, Penza S, Andritsos LA, Devine SM (2014) Aprepitant for the control of delayed nausea and vomiting associated with the use of high-dose melphalan for autologous peripheral blood stem cell transplants in patients with multiple myeloma: a phase II study. Support Care Cancer 22(11):2911–2916

    Article  PubMed  Google Scholar 

  52. dos Santos LV, Souza FH, Brunetto AT, Sasse AD, da Silveira Nogueira Lima JP (2012) Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting: a systematic review. J Natl Cancer Inst 104(17):1280–1292

    Article  PubMed  Google Scholar 

  53. Chawla SP, Grunberg SM, Gralla RJ, Hesketh PJ, Rittenberg C, Elmer ME, Schmidt C, Taylor A, Carides AD, Evans JK, Horgan KJ (2003) Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting. Cancer 97(9):2290–2300

    Article  CAS  PubMed  Google Scholar 

  54. Leal AD, Kadakia KC, Looker S, Hilger C, Sorgatz K, Anderson K, Jacobson A, Grendahl D, Seisler D, Hobday T, Loprinzi CL (2014) Fosaprepitant-induced phlebitis: a focus on patients receiving doxorubicin/cyclophosphamide therapy. Support Care Cancer 22(5):1313–1317

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Aapro MS, Walko CM (2010) Aprepitant: drug-drug interactions in perspective. Ann Oncol 21(12):2316–2323

    Article  CAS  PubMed  Google Scholar 

  56. Shadle CR, Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, Evans JK, Blum RA (2004) Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol 44(3):215–223

    Article  CAS  PubMed  Google Scholar 

  57. de Jonge ME, Huitema AD, Holtkamp MJ, van Dam SM, Beijnen JH, Rodenhuis S (2005) Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism. Cancer Chemother Pharmacol 56(4):370–378

    Article  PubMed  Google Scholar 

  58. Rapoport BL, Weinstein C, Camacho ES, Khanani SA, Beckford-Brathwaite E, Kevill L, Vallejos W, Liang LW, Noga SJ (2015) A phase III, randomized, double-blind study of single-dose intravenous fosaprepitant in preventing chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy. J Clin Oncol 33(Suppl; abstr 9629)

    Google Scholar 

  59. Albany C, Brames MJ, Fausel C, Johnson CS, Picus J, Einhorn LH (2012) Randomized, double-blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a hoosier oncology group study. J Clin Oncol 30(32):3998–4003

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Oncology, The Medical Oncology Center of Rosebank, 129 Oxford Road, Saxonwold, Johannesburg, South Africa

    Bernardo Leon Rapoport Dip. in Med., M. Med.

Authors
  1. Bernardo Leon Rapoport Dip. in Med., M. Med.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernardo Leon Rapoport Dip. in Med., M. Med. .

Editor information

Editors and Affiliations

  1. Indiana University School of Medicine, South Bend, Indiana, USA

    Rudolph M. Navari

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Rapoport, B.L. (2016). The Role of Neurokinin-1 Receptor Antagonists in CINV. In: Navari, R. (eds) Management of Chemotherapy-Induced Nausea and Vomiting. Adis, Cham. https://doi.org/10.1007/978-3-319-27016-6_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-27016-6_5

  • Published:

  • Publisher Name: Adis, Cham

  • Print ISBN: 978-3-319-27014-2

  • Online ISBN: 978-3-319-27016-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation