Этелкальцетид в лечении вторичного гиперпаратиреоза у пациентов на программном гемодиализе: обзор клинических данных и место в терапии


DOI: https://dx.doi.org/10.18565/nephrology.2020.2.74-83

Г.В. Волгина, Н.А. Михайлова

1) ФГБОУ ВО «Московский государственный медико-стоматологический университет им. А.И. Евдокимова» МЗ РФ, Москва, Россия; 2) ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» МЗ РФ, кафедра нефрологии и гемодиализа, Москва, Россия
Вторичный гиперпаратиреоз (ВГПТ) широко распространен среди пациентов, получающих поддерживающий гемодиализ (ПГД), и связан с неблагоприятными исходами. В настоящее время тактика лечения ВГПТ заключается в снижении уровня циркулирующего фосфата с помощью пероральных фосфат-связывающих препаратов и в снижении уровня паратиреоидного гормона (ПТГ) с помощью кальцимиметиков – цинакальцета (ЦК), этелкальцетида (ЭК) – и/или аналогов витамина D.
В данной статье представлен краткий обзор патогенеза ВГПТ при хронической болезни почек (ХБП), при этом особое внимание уделено основным молекулярным регуляторам, на которые действуют кальцимиметики. Этелкальцетид представляет собой новый внутривенный кальцимиметик третьей генерации, эффективно снижавший уровень ПТГ в клинических исследованиях при введении 3 раза в неделю. Помимо повышенной приверженности лечению для ЭК характерна более высокая, чем у ЦК, эффективность в подавлении секреции ПТГ. Дополнительные клинические эффекты этого препарата включают снижение уровня циркулирующего фосфата и FGF-23, благоприятное влияние на маркеры костного обмена. Однако, несмотря на в/в введение ЭК, частота случаев тошноты и рвоты при его применении, по-видимому, сходна с таковой для ЦК. Вероятно, этелкальцетид может применяться в лечении ГД пациентов с тяжелым ВГПТ или с гиперкальциемией или гиперфосфатемией, получающих активные метаболиты витамина D. Однако его использование должно как минимум частично ограничиваться из-за риска гипокальциемии и возможного удлинения электрокардиографического интервала QT у пациентов, исходно имеющих низкий уровень кальция и нарушения сердечной проводимости. Обладая эффективностью в качестве препарата для снижения уровня ПТГ, ЭК представляет собой новый, потенциально перспективный терапевтический подход к лечению ВГПТ у пациентов на ПГД. Статья обобщает имеющиеся на сегодня данные о результатах клинических исследований нового внутривенного кальцимиметика третьего поколения.

Литература



  1. Block G.A., Klassen P.S., Lazarus J.M., et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J. Am. Soc. Nephrol. 2004;15(8):2208–2218.

  2. Tentori F., Wang M., Bieber B.A., et al. Recent changes in therapeutic approaches and association with outcomes among patients with secondary hyperparathyroidism on chronic hemodialysis: the DOPPS study. Clin. J. Am. Soc. Nephrol. 2015;10(1):98–109.

  3. Floege J., Kim J., Ireland E., et al. Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population. Nephrol. Dial. Transplant. 2011;26(6):1948–1955.

  4. Palmer S.C., McGregor D.O., Macaskill P., et al. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med. 2007; 147(12):840–853.

  5. Isakova T., Xie H., Yang W., et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305:2432–2439.

  6. Nasrallah M.M., El-Shehaby A.R., Salem M.M., et al. Fibroblast growth factor-23 (FGF-23) is independently correlated to aortic calcification in haemodialysis patients. Nephrol. Dial. Transplant 2010;25:2679–2685

  7. Scialla J.J., Xie H., Rahman M., et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J. Am. Soc. Nephrol. 2014;25(2):349–360.

  8. Ketteler M., Block G.A., Evenepoel P., et al. Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKDMBD) guideline update: what’s changed and why it matters. Kidney Int. 2017;92(1):26–36.

  9. Г.В. Волгина, Н.А. Михайлова, Е.В. Шутов, О.Н. Котенко. Алгоритмы лечения вторичного гиперпаратиреоза у пациентов с ХБП 5Д стадии. Клиническая нефрология, 2017;4:21–24.

  10. Zhang Q., Li M., You L., et al. Effects and safety of calcimimetics in end stage renal disease patients with secondary hyperparathyroidism: a meta-analysis. PLoS One. 2012;7(10):e48070.

  11. Behets G.J., Spasovski G., Sterling L.R., et al. Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism. Kidney Int. 2015;87:846–856.

  12. Wetmore J.B., Liu S., Krebill R., et al. Effects of cinacalcet and concurrent low-dose vitamin D on FGF-23 levels in ESRD. Clin. J. Am. Soc. Nephrol. 2010;5(1):110–116.

  13. Parfrey P.S., Chertow G.M., Block G.A., et al. The clinical course of treated hyperparathyroidism among patients receiving hemodialysis and the effect of cinacalcet: the EVOLVE trial. J. Clin. Endocrinol. Metab. 2013;98(12):4834–4844.

  14. EVOLVE Trial Investigators. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N. Engl. J.Med. 2012;367(26):2482–2494.

  15. Floege J., Kubo Y., Floege A., et al. The effect of cinacalcet on calcific uremic arteriolopathy events in patients receiving hemodialysis: the EVOLVE trial. Clin J. Am. Soc. Nephrol. 2015;10(5):800–807

  16. Ureña-Torres P.A., Floege J., Hawley C.M., et al. Protocol adherence and the progression of cardiovascular calcification in the ADVANCE study. Nephrol. Dial. Transplant. 2013;28(1):146–152.

  17. Raggi P., Chertow G.M., Torres P.U., et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol. Dial. Transplant. 2011;26(4):1327–1339.

  18. Park H., Rascati K.L., Lawson K.A., et al. Adherence and persistence to prescribed medication therapy among Medicare part D beneficiaries on dialysis: comparisons of benefit type and benefit phase. J. Manag. Care Spec. Pharm. 2014;20(8):862–876.

  19. Chiu Y.W., Teitelbaum I., Misra M., et al. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin J. Am. Soc. Nephrol. 2009;4(6):1089–1096.

  20. Gincherman Y., Moloney K., McKee C., Coyne D.W. Assessment of adherence to cinacalcet by prescription refill rates in hemodialysis patients. Hemodial. Int. 2010;14(1):68–72.

  21. de Francisco A.L., Gillespie I.A., Gioni I., et al. Anti-parathyroid treatment effectiveness and persistence in incident haemodialysis patients with secondary hyperparathyroidism. Nefrologia. 2016;36:164–175.

  22. Burnier M., Pruijm M., Wuerzner G., Santschi V. Drug adherence in chronic kidney diseases and dialysis. Nephrol. Dial.Transplant. 2015;30(1):39–44.

  23. Ghimire S., Castelino R.L., Lioufas N.M., et al. Nonadherence to medication therapy in haemodialysis patients: a systematic review. PLoS One. 2015;10(12):e0144119.

  24. Kim S.M., Long J., Montez-Rath M.E., et al. Rates and outcomes of parathyroidectomy for secondary hyperparathyroidism in the United States. Clin. J. Am. Soc. Nephrol. 2016;11(7):1260–1267.

  25. Tominaga Y., Kakuta T., Yasunaga C., et al. Evaluation of parathyroidectomy for secondary and tertiary hyperparathyroidism by the Parathyroid Surgeons’ Society of Japan. Ther. Apher. Dial. 2016;20(1):6–11.

  26. Ishani A, Liu J, Wetmore JB, et al. Clinical outcomes after parathyroidectomy in a nationwide cohort of patients on hemodialysis. Clin J Am Soc Nephrol. 2015;10(1):90–97.

  27. Wetmore J.B., Liu J., Do T.P., et al. Changes in secondary hyperparathyroidism-related biochemical parameters and medication use following parathyroidectomy. Nephrol. Dial. Transplant. 2016;31(1):103–111

  28. Blair H.A. Etelcalcetide: first global approval. Drugs. 2016;76:1787–1792.

  29. Brown E.M., Gamba G., Riccardi D., et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature. 1993, 366:575–580.

  30. Leach K., Hannan F.M., Josephs T.M., et al. International union of basic and clinical pharmacology. CVIII. Calcium-sensing receptor nomenclature, pharmacology, and function. Pharmacol. Rev. 2020,72:558–604. DOI: 10.1124/pr.119.018531

  31. Harrington P.E., Fotsch C. Calcium sensing receptor activators: calcimimetics. Curr. Med. Chem. 2007;14:3027–3034.

  32. Eidman K.E., Wetmore J.B. Treatment of secondary hyperparathyroidism: How do cinacalcet and etelcalcetide differ? Seminars in Dialysis. 2018;31:440–444.

  33. Wu В., Melhem M., Subramanian R., et al. Clinical pharmacokinetics and pharmacodynamics of etelcalcetide, a novel calcimimetic for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on hemodialysis. The Journal of Clinical Pharmacology Epub. 2018 Mar 13. DOI: 10.1002/jcph.1090

  34. Kroenke M.A., Weeraratne D.K., Deng H., et al. Clinical immunogenicity of the d-amino acid peptide therapeutic etelcalcetide: method development challenges and anti-drug antibody clinical impact assessments. J. Immunol. Methods. 2017;445:37–44.

  35. Subramanian R., Zhu X., Kerr S.J., et al. Nonclinical pharmacokinetics, disposition, and drug-drug interaction potential of a novel d-amino acid peptide agonist of the calcium-sensing receptor AMG 416 (etelcalcetide). Drug. Metab . Dispos. 2016;44(8):1319–1331.

  36. Edson K.Z., Wu B.M., Iyer A., et al. Determination of etelcalcetide biotransformation and hemodialysis kinetics to guide the timing of its dosing. Kidney Int. 2016;1(1):24–33.

  37. Wu L., Melhem M., Subramanian R., Wu B. Drug disposition model of radiolabeled etelcalcetide in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis. J. Pharmacokinet Pharmacodyn. 2017;44(1):43–53.

  38. Михайлова Н.А. Этелкальцетид – инновационный препарат для лечения вторичного гиперпаратиреоза у больных на программном гемодиализе. Клиническая нефрология. 2018,1:74–79.

  39. Martin K.J., Pickthorn K., Huang S., et al. AMG 416 (velcalcetide) is a novel peptide for the treatment of secondary hyperparathyroidism in a single-dose study in hemodialysis patients. Kidney Int. 2014;85(1):191–197.

  40. Bell G., Huang S., Martin K.J., Block G.A. A randomized, double-blind, phase 2 study evaluating the safety and efficacy of AMG 416 for the treatment of secondary hyperparathyroidism in hemodialysis patients. Curr. Med. Res. Opin. 2015;31(5):943–952.

  41. Fukagawa M., Yokoyama K., Shigematsu T., et al. A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients. Nephrol. Dial. Transplant. 2017;32(10):1723–1730.

  42. Block G.A., Bushinsky D.A., Cheng S., et al. Effect of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: a randomized clinical trial. JAMA. 2017;317(2):156–164.

  43. Wolf M., Block G.A., Chertow G.M., et al. Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis. Clinical Kidney Journal. 2020,13(1):75–84. DOI: 10.1093/ckj/sfz034

  44. Russo D., Tripepi R., Malberti F., et al. Etelcalcetide in patients on hemodialysis with severe secondary hyperparathyroidism. Multicenter study in “real life”. J. Clin. Med. 2019,8:1066–74. DOI:10.3390/jcm8071066

  45. Fernández-Martín J.L., Martínez-Camblor P., Dionisi M.P., et al. Improvement of mineral and bone metabolism markers is associated with better survival in haemodialysis patients: the COSMOS study. Nephrol. Dial. Transplant. 2015, 30:1542–1551.

  46. Bushinsky D.A., Chertow G.M., Cheng S., et al. One-year safety and efficacy of intravenous etelcalcetide in patients on hemodialysis with secondary hyperparathyroidism. Nephrol. Dial. Transplant. 2019:1–10. DOI: 10.1093/ndt/gfz039

  47. Fielden M.R., Dean C.Jr., Black K., et al. Nonclinical safety profile of etelcalcetide, a novel peptide calcimimetic for the treatment of secondary hyperparathyroidism. Int. J. Toxicol. 2016;35:294–308.

  48. Rottembourg J., Ure-na-Torres P., Toledano D., et al. Factors associated with parathyroid hormone control in haemodialysis patients with secondary hyperparathyroidism treated with cinacalcet in real-world clinical practice: Mimosa study. Clinical Kidney Journal. 2019:1–9. DOI: 10.1093/ckj/sfz021

  49. De Geest S., Sabate E. Adherence to long-term therapies: evidence for action. Eur. J. Cardiovasc. Nurs. 2003;2:323

  50. Arenas M.D., Rodelo-Haad C., Pendon-Ruiz de Mier M.V., Rodriguez M. Control of hyperparathyroidism with the intravenous calcimimetic etelcalcetide in dialysis patients adherent and non-adherent oral calcimimetics. Clin. Kidney J. 2020. DOI:10.1093/ckj/sfaa005

  51. Burnier M., Pruijm M., Wuerzner G., et al. Drug adherence in chronic kidney diseases and dialysis. Nephrol. Dial. Transplant. 2015;30:39–44.

  52. Xipell M., Montagud-Marrahi E., Rubio M.V., et al. Improved control of secondary hyperparathyroidism in hemodialysis patients switching from oral cinacalcet to intravenous etelcalcetide, especially in nonadherent patients. Blood Purif. 2019. DOI: 10.1159/000496562

  53. Sprenger-Mähr Н., Zitt Е., Kronbichler А., et al. A hemodialysis patient with bone disease after pregnancy: a case report. BMC Nephrology. 2019,20:425. Doi:10.1186/s12882-019-1603-8

  54. Walter S., Baruch A., Dong J., et al. Pharmacology of AMG 416 (velcalcetide), a novel peptide agonist of the calcium-sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients. J. Pharmacol. Exp. Ther. 2013;346(2):229–240.

  55. Yoshimura K., Funakoshi Y.,Terawaki H. Dramatic Regression of Parathyroid Gland Swelling After Conversion of Calcimimetic Medication From Cinacalcet to Etelcalcetide. Therapeutic Apheresis and Dialysis 2018. Еpub. DOI: 10.1111/1744-9987.12701

  56. Yu L., Tomlinson J.E., Alexander S.T., et al. Etelcalcetide, a novel calcimimetic, prevents vascular calcification in a rat model of renal insufficiency with secondary hyperparathyroidism. Calcif Tissue Int. 2017;101(6):641–653.

  57. Zucchelli P., Santoro A., Zucchelli A., et al. Long‐term effects of parathyroidectomy on cardiac and autonomic nervous system functions in haemodialysis patients. Nephrol. Dial. Transpl. 1988,3:45–50.

  58. Conzo G., Perna A.F., Savica V., et al. Impact of parathyroidectomy on cardiovascular outcomes and survival in chronic hemodialysis patients with secondary hyperparathyroidism. A retrospective study of 50 cases prior to the calcimimetics era. BMC Surg. 2013,13 (2):S4.

  59. Chang T.I., Abdalla S., London G.M., et al. The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial. J. Hum. Hypertens. 2016;30:204–209.

  60. Simeoni М., Perna A.F., Fuiano G. Secondary Hyperparathyroidism and Hypertension: An Intriguing Couple. J. Clin. Med. 2020,9:629–37. DOI:10.3390/jcm9030629

  61. Li X., Yu L., Asuncion F., et al. Etelcalcetide (AMG 416), a peptide agonist of the calcium-sensing receptor, preserved cortical bone structure and bone strength in subtotal nephrectomized rats with established secondary hyperparathyroidism. Bone. 2017;105:163–172.

  62. Díaz-Tocados J.M., Rodríguez-Ortiz M.E., Almadén Y., et al. Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration. Kidney Int. 2019;95:1064–1078.

  63. Shigematsu T., Fukagawa M., Yokoyama K., et al (2018) Effects of the intravenous calcimimetic etelcalcetide on bone turnover and serum fibroblast growth factor 23: post hoc analysis of an openlabel study. Clin. Ther. 40:2099–2111.

  64. Palmer S.C., Mavridis D., Johnson D.W., et al. Comparative effectiveness of calcimimetic agents for secondary hyperparathyroidism in adults: a systematic review and network meta-analysis. Am. J. Kidney Dis. 2020, Epub. DOI:10.1053/j.ajkd.2020.02.439

  65. Flueckiger P., Pastan S., Goyal A., et al. Associations of ECG interval prolongations with mortality among ESRD patients evaluated for renal transplantation. Ann.Transplant. 2014;19:257–268.

  66. Block G.A., Bushinsky D.A., Cunningham J., et al. Effect of Etelcalcetide vs Placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism. Two Randomized Clinical Trials. JAMA. 2017;317(2):146–155.

  67. Ansell D., Feehally J., Feest T.G., et al. UK Renal Registry 11th Annual Report. Bristol: The Renal Association; 2008. https://www.renalreg.org/wp-content/uploads/2014/09/Report2008.pdf. Accessed November 15, 2017.

  68. Brown D.W., Giles W.H., Greenlund K.J., et al. Impaired fasting glucose, diabetes mellitus, and cardiovascular disease risk factors are associated with prolonged QTc duration. Results from the Third National Health and Nutrition Examination Survey. J. Cardiovasc. Risk. 2001;8(4):227–233.

  69. Marfella R., Rossi F., Giugliano D. Hyperglycemia and QT interval: time for re-evaluation. Diabetes Nutr. Metab. 2001;14(2):63–65.

  70. Gastaldelli A., Emdin M., Conforti F., et al. Insulin prolongs the QTc interval in humans. Am. J. Physiol. Cell Physiol. 2000;279(6):R2022–R2025.

  71. Kacheva S., Karges B., Göller K., et al. QT prolongation caused by insulin-induced hypoglycaemia – an interventional study in 119 individuals. Diabetes Res. Clin. Pract. 2017;123:165–172.

  72. Basiaga S.B., Hage D.S. Chromatographic studies of changes in binding of sulfonylurea drugs to human serum albumin due to glycation and fatty acids.J. Chromatogr. B. 2010;878(30):3193–3197.

  73. Lin C.S., Lin S.H., Cheng S.M., et al. Reversible heart failure in a hypocalcemic patient. Acta Cardiol. Sin. 2009;25:47–51.


Об авторах / Для корреспонденции


Волгина Галина Владимировна – д.м.н., проф. кафедры нефрологии ФПДО ФГБОУ ВО МГМСУ им. А.И. Евдокимова МЗ РФ; Москва, Россия. E-mail: volginagv@mail.ru
Михайлова Наталия Алексеевна – к.м.н., доцент кафедры нефрологии и гемодиализа ГБОУ ДПО РМАНПО МЗ РФ; Москва, Россия.
Е-mail: natmikhailova@mail.ru


Похожие статьи


Бионика Медиа