Пероральная комбинация нетупитанта и палоносетрона для профилактики тошноты и рвоты, индуцированной химиотерапией

Тошнота и рвота являются наиболее частыми и тягостными осложнениями химиотерапии. Неконтролируемая тошнота и рвота приводят к значительному снижению качества жизни больных, нутритивной недостаточности, нарушению режима химиотерапии. Тошнота и рвота ухудшают результат химиотерапии и прогноз течения болезни. В клинических исследованиях противорвотных препаратов в качестве первичной конечной точки используется показатель полного ответа. Полный ответ - это отсутствие тошноты и рвоты и потребности в дополнительных противорвотных препаратах. Пероральная комбинация нетупитанта и палоносетрона является современным препаратом для профилактики тошноты и рвоты, индуцированной химиотерапией. В состав препарата входят высокоселективный антагонист NK1-рецепторов нетупитант в дозе 300 мг и антагонист 5-НТЗ-рецепторов палоносетрон в дозе 0,5 мг. Комбинация нетупитанта и палоносетрона обладает высокой комплаентностью, назначается однократно перед химиотерапией, она позволяет добиться полного контроля острой (0-24 ч) и отсроченной (24-120 ч) тошноты и рвоты при высокоэметогенной химиотерапии. В рандомизированном исследовании (n = 1455) при химиотерапии АС (доксорубицин + циклофосфамид) комбинация нетупитанта и палоносетрона привела к полному ответу в течение общей фазы (0-120 ч) у 73,3% пациентов. 78,4% пациентов при комбинации нетупитант / палоносетрон испытали отсутствие влияния на повседневную жизнь из-за тошноты и рвоты. В наблюдательном исследовании реальной клинической практики (n = 1 197) комбинация нетупитанта и палоносетрона при режиме химиотерапии АС (доксорубицин + циклофосфамид) полный ответ в течение общей фазы (0-120 ч) был достигнут у 81% больных. Нежелательные явления при применении комбинации нетупитант и палоносетрон минимальны, отмечались запор в 1-8% случаев, головная боль в 1,4-3,6% случаев.

1. Владимирова Л.Ю., Гладков О.А., Королева И.А., Румянцев А.А., Семиглазова Т.Ю., Трякин А.А. и др. Практические рекомендации по профилактике и лечению тошноты и рвоты у онкологических больных. Злокачественные опухоли. 2021;11(3s2-2):25-38. https://doi.org/10.18027/2224-5057-2021-11-3s2-37.

2. Warr D.G. Chemotherapy-and cancer-related nausea and vomiting. Curr Oncol. 2008;15(Suppl.1):4-9. https://doi.org/10.3747/co.2008.171.

3. Roila F., Herrstedt J., Aapro M., Gralla R.J., Einhorn L.H., Ballatori E. et al. 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. 2010;21(5):v232-243. https://doi.org/10.1093/annonc/mdq194.

4. Herrstedt J., Roila F., Warr D., Celio L., Navari R.M., Hesketh P.J. et al. Multinational Association of Supportive Care in Cancer. MASCC/ESMO antiemetic guideline 2016. With updates in 2019. Available at: https://mascc.org/assets/Guidelines-Tools/mascc_antiemetic_guidelines_english_v.1.5SEPT29.2019.pdf.

5. Hesketh P.J., Kris M.G., Basch E., Bohlke K., Barbour S.Y., Clark-Snow R.A. et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020;38(24):2782-2797. https://doi.org/10.1200/JCO.20.01296.

6. Ettinger D.S., Berger M.J., Anand S., Barbour S., Bergsbaken J., Bowman C. et al. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Antiemesis. Version 2.2020. Available at: https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf.

7. Rojas C., Slusher B.S. Pharmacological mechanisms of 5-HT3 and tachykinin NK1 receptor antagonism to prevent chemotherapy-induced nausea and vomiting. Eur J Pharmacol. 2012;684(1-3):1-7. https://doi.org/10.1016/j.ejphar.2012.01.046.

8. Bosnjak S.M., Gralla R.J., Schwartzberg L. Prevention of chemotherapy-induced nausea: the role of neurokinin-1 (NK1) receptor antagonists. Support Care Cancer 2017;25(5):1661-1671. https://doi.org/10.1007/s00520-017-3585-z.

9. Garcia-Recio S., Gascon P. Biological and Pharmacological aspects of the NK1-receptor. BioMed Res Int. 2015;2015:495704. https://doi.org/10.1155/2015/495704.

10. Sandweiss A.J., Vanderah T.W. The pharmacology of neurokinin receptors in addiction: prospects for therapy. Subst Abuse and Rehabil. 2015(6):93-102. https://doi.org/10.2147/SAR.S70350.

11. Saito R., Takano Y., Kamiya H. Roles of substance P and NK1 receptor in brainstem in the development of emesis. J Pharmacol Sci. 2003;91(2):87-94. https://doi.org/10.1254/jphs.91.87.

12. Demol P., Ruoff H.J., Weihrauch T.R. Rational pharmacotherapy of gastrointestinal motility disorders. Eur J Pediatr. 1989;148(6):489-495. https://doi.org/10.1007/BF00441540.

13. Grunberg S.M., Deuson R.R., Mavros P., Geling O, Hansen M, Cruciani G, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer. 2004;100(10):2261-2268. https://doi.org/10.1002/cncr.20230.

14. Wong E.H.F., Clark R., Leung E., Loury D., Bonhaus D.W., Jakeman L. et al. The interaction of RS 25259-197, a potent and selective antagonist, with 5-HT3 receptors, in vitro. Br J Pharmacol. 1995;114(4):851-859. https://doi.org/10.1111/j.1476-5381.1995.tb13282.x.

15. Stoltz R., Cyong J.C., Shah A., Parisi S. Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in US and Japanese healthy subjects. J Clin Pharmacol. 2004;44(5):520-531. https://doi.org/10.1177/0091270004264641.

16. Aapro M.S., Grunberg S.M., Manikhas G.M., Olivares G., Suarez T., Tjulandin S.A. et al. A phase III, double-blind, randomized trial of palono-setron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17(9):1441-1449. https://doi.org/10.1093/annonc/mdl137.

17. Eisenberg P., Figueroa-Vadillo J., Zamora R., Charu V., Hajdenberg J., Cartmell A. et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-НТ3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98(ll):2473-2482. https://doi.org/l0.l002/cncr.ll8l7.

18. Saito M., Aogi K., Sekine I., Yoshizawa Н., Yanagita Y., Sakai Н. et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol. 2009;l0(2):ll5-l24. https://doi.org/l0.l0l6/sl470-2045(08)703l3-9.

19. Likun Z., Xiang J., Xin D., Tao Z.L. A Systematic Review and Meta-Analysis of Intravenous Palonosetron in the Prevention of Chemotherapy-Induced Nausea and Vomiting in Adults. Oncologist. 20ll;l6(2):207-2l6. https://doi.org/l0.l634/theoncologist.20l0-0l98.

20. Grunberg S., Chua D., Maru A., Dinis J., DeVandry S., Boice J.A. et al. SingleDose Fosaprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting Associated With Cisplatin Therapy: Randomized, DoubleBlind Study Protocol - EASE. J Clin Oncol. 20ll;29(ll):l495-l50l. https://doi.org/l0.l200/jco.20l0.3l.7859.

21. Hesketh PJ., Grunberg S.M., Gralla RJ., Warr D.G., Roila F., de Wit R. et al. The oral neurokinin-l 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. 2003;2l(22):4ll2-4ll9. https://doi.org/l0.l200/JCO.2003.0l.095.

22. Poli-Bigelli S., Rodrigues-Pereira J., Carides A.D., Julie Ma G., Eldridge K., Hipple A. et al. Aprepitant Protocol 054 Study Group. Addition of the neurokinin l 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. 2003;97(l2):3090-3098. https://doi.org/l0.l002/cncr.ll433.

23. Warr D.G., Hesketh P.J., Gralla R.J., Muss H.B., Herrstedt J., Eisenberg P.D. et al. 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. 2005;23(l2):2822-2830. https://doi.org/l0.l200/JCO.2005.09.050.

24. Grunberg S., Chua D., Maru A., Dinis J., DeVandry S., Boice J.A. et al. 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. 20ll;29(ll):l495-l50l. https://doi.org/l0.l200/JCO.20l0.3l.7859.

25. Rapoport B.L., Chasen M.R., Gridelli C., Urban L., Modiano M.R., Schnadig I.D. et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol. 20l5;l6(9):l079-l089. https://doi.org/l0.l0l6/Sl470-2045(l5)00035-2.

26. Suzuki K., Yamanaka T., Hashimoto H., Shimada Y., Arata K., Matsui R. et al. Randomized, double-blind, phase III trial of palonosetron versus granise-tron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study. Ann Oncol. 20l6;27(8):l60l-l606. https://doi.org/l0.l093/annonc/mdw220.

27. Navari R.M., Gray S.E., Kerr A.C. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol. 20ll;9(5):l88-l95. https://doi.org/l0.l0l6/j.suponc.20ll.05.002.

28. Aapro M., Caprariu Z., Chilingirov P., Chrapava M., Curca R.O., Gales L. et al. Assessing the impact of antiemetic guideline compliance on prevention of chemotherapy-induced nausea and vomiting: Results of the nausea/ emesis registry in oncology (NERO). Eur J Cancer. 2022;(l66):l26-l33. https://doi.org/l0.l0l6/j.ejca.2022.0l.028.

29. Hesketh P.J., Rossi G., Rizzi G., Palmas M., Alyasova A., Bondarenko I. et al. Efficacy and safety of NEPA, an oral combination of netupitant and palo-nosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol. 20l4;25(7):l340-l346. https://doi.org/l0.l093/annonc/mdull0.

30. Aapro M., Rugo H., Rossi G., Rizzi G., Borroni M.E., Bondarenko I. et al. 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. 20l4;25(7):l328-l333. https://doi.org/l0.l093/annonc/mdul0l.

31. Gralla R.J., Bosnjak S.M., Hontsa A., Balser C., Rizzi G., Rossi G. et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol. 20l4;25(7):l333-l339. https://doi.org/l0.l093/annonc/mdu096.

32. Rugo H.S., Rossi G., Rizzi G., Aapro M. Efficacy of NEPA (netupitant/palo-nosetron) across multiple cycles of chemotherapy in breast cancer patients: A subanalysis from two phase III trials. Breast. 20l7;(33):76-82. https://doi.org/l0.l0l6/j.breast.20l7.02.0l7.

33. Zhang L., Lu S., Feng J., Dechaphunkul A., Chang J., Wang D. et al. A randomized phase III study evaluating the efficacy of single-dose NEPA, a fixed antiemetic combination of netupitant and palonosetron, versus an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC). Ann Oncol. 20l8;29(2):452-458. https://doi.org/l0.l093/annonc/mdx698.

34. Zelek L., Debourdeau P., Bourgeois H., Wagner J.P., Brocard F., Lefeuvre-Plesse C. et al. A Pragmatic Study Evaluating NEPA Versus Aprepitant for Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy. Oncologist. 202l;26(l0):el870-el879. https://doi.org/l0.l002/onco.l3888.

35. Karthaus M., Oskay-Ozcelik G., Wulfing P., Hielscher C., Guth D., Zahn M.O. et al. Real-world evidence of NEPA, netupitant-palonosetron, in chemotherapy-induced nausea and vomiting prevention: effects on quality of life. Future Oncol. 2020;l6(l4):939-953. https://doi.org/l0.22l7/fon-2020-0l87.

36. Schilling J., Kurbacher C.M., Hanusch C., Busch S., Hollander M., Kreiss-Sender J. et al. Quality of Life Effects of an Oral Fixed Combination of Netupitant and Palonosetron in Chemotherapy-Induced Nausea and Vomiting Prevention: Real-World Evidence in Patients with Breast Cancer Receiving Anthracycline-Cyclophosphamide-Based Chemotherapy. Breast Care (Basel). 2022;l7(2):l30-l36. https://doi.org/l0.ll59/0005l489l.

37. De Luca R., Volpe C., Mistretta O., Paci R., Ferrera G., Caputo V., Rosati G., Cicero G. NEPA (netupitant/palonosetron) for the antiemetic prophylaxis of nausea and vomiting induced by chemotherapy (CINV) with Folfirinox and Folfoxiri even during the COVID-l9 pandemic: a real-life study. Eur Rev Med Pharmacol Sci. 202l;25(l6):53l0-53l7. https://doi.org/l0.26355/eurrev_202l08_26552.

38. Botteman M., Nickel K., Corman S., Turini M., Binder G. Cost-effectiveness of a fixed combination of netupitant and palonosetron (NEPA) relative to aprepitant plus granisetron (APR + GRAN) for prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a trial-based analysis. Support Care Cancer. 2020;28(2):857-866. https://doi.org/l0.l007/s00520-0l9-04824-y.