porozendoОстеопороз и остеопатииOsteoporosis and Bone Diseases2072-26802311-0716Endocrinology Research Centre10.14341/osteo12309porozendo-12309Research ArticleНаучный обзорReviewНовый кальцимиметик эвокальцет для лечения вторичного гиперпаратиреоза на фоне хронической болезни почек с небольшим влиянием на желудочно-кишечный тракт и изоформы цитохрома р450 in vivo и in vitroA novel calcimimetic evocalcet for the management of secondary hyperparathyroidism with little effect on the gastrointestinal tract and cyp isozymes in vivo and in vitrohttps://orcid.org/0000-0001-8817-1901ЕгшатянЛилит ВаниковнаEgshatyanLilit V.

к.м.н.

MD, PhD

lilit.egshatyan@yandex.ruГБУЗ “Московский клинический научный центр им. А.С. Логинова” ДЗМ; ФГБУ “Национальный медицинский исследовательский центр эндокринологии” МЗ РФ; ФГБОУ ВО “Московский государственный медико-стоматологический университет им. А.И. Евдокимова”РоссияThe Loginov Moscow Clinical Scientific Center of Moscow Health Department; Endocrinology Research Centre, Ministry of Health of Russia; А.I. Evdokimov Moscow State University of Medicine and DentistryRussian Federation2019010620202232733Copyright © Егшатян Л.В., 20192019Егшатян Л.В.Egshatyan L.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.osteo-endojournals.ru/jour/article/view/12309

Цели медикаментозного лечения вторичного гиперпаратиреоза у пациентов с хронической болезнью почек направлены на предотвращение прогрессирования заболевания и подавление активности околощитовидных желез с помощью модуляции рецепторов к витамину D и кальций-чувствительных рецепторов. В настоящее время для лечения вторичного гиперпаратиреоза на фоне хронической болезни почек широко используется пероральный кальцииметик – цинакальцет. Однако применение цинакальцета связано с желудочно-кишечными неблагоприятными событиями, что формирует когорту пациентов, рефрактерных к терапии. Цинакальцет также ингибирует цитохром P450 (CYP) 2D6 в печени. Для решения этих проблем был создан новый таблетированный кальцимиметик — эвокальцет (MT-4580/KHK7580). Выявлено, что эвокальцет значительно снижает концентрации паратиреоидного гормона как у нормальных, так и у 5/6 нефрэктомированных крыс. Эффективность препарата была продемонстрирована как в открытом многоцентровом исследовании 3 фазы по оценке долгосрочной эффективности и безопасности эвокальцета у японских пациентов, получающих заместительную почечную терапию гемодиализом, так и в клинической практике у пациентов на перитонеальном диализе. Обнаружено, что эвокальцет практически не влияет на опорожнение желудка, меньше индуцирует рвоту и в целом развитие желудочно-кишечных нежелательных явлений, а фармакологические эффекты его наблюдаются на более низких дозах из-за более высокой биодоступности в сравнении с цинакальцетом. Кроме того, эвокальцет не показал существенного прямого подавления активности изоформ цитохрома 450. Эти результаты показывают, что эвокальцет может стать лучшей альтернативой цинакальцету при непереносимости последнего, с более широким спектром безопасности.

In the treatment of secondary hyperparathyroidism of end-stage chronic kidney disease, vitamin D receptor activation and allosteric modulators of the calcium-sensing receptor - inhibit glandular hyperplasia; reduce parathyroid hormone levels, impact on bone turnover and mineral density. Cinacalcet, an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism in chronic kidney disease. Nevertheless, some patients remain refractory to the treatment, as the dose of cinacalcet cannot be sufficiently increased due to gastrointestinal symptoms and it strong inhibits of cytochrome P450 (CYP) 2D6. In order to resolve this issue, was develop a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of chronic kidney disease induced by 5/6 nephrectomy, and in multicenter, open-label study phase 3, and in clinical practice oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone. Evocalcet also demonstrated the less induction of emesis and gastro-intestinal effects, and its pharmacological effects were observed at lower doses because of its higher bioavailability than cinacalcet. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro. These findings suggest that evocalcet can be a better alternative to cinacalcet with a wider safety margin.

вторичный гиперпаратиреозхроническая болезнь почекпаратиреоидный гормонкальцимиметикцинакальцетэтелкальцетидэвокальцетsecondary hyperparathyroidismchronic kidney diseaseparathyroid hormonecalcimimeticcinacalcetetelcalcetideevocalcetReferencesGoodman WG, Quarles LD. Development and progression of secondary hyperparathyroidism in chronic kidney disease: lessons from molecular genetics. Kidney Int. 2008;74(3):276-288. doi: https://doi.org/10.1038/sj.ki.5002287Goodman WG, Quarles LD. Development and progression of secondary hyperparathyroidism in chronic kidney disease: lessons from molecular genetics. Kidney Int. 2008;74(3):276-288. doi: https://doi.org/10.1038/sj.ki.5002287Tentori F, Blayney MJ, Albert JM, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2008;52(3):519-530. doi: https://doi.org/10.1053/j.ajkd.2008.03.020Tentori F, Blayney MJ, Albert JM, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2008;52(3):519-530. doi: https://doi.org/10.1053/j.ajkd.2008.03.020Taniguchi M, Fukagawa M, Fujii N, et al. Serum phosphate and calcium should be primarily and consistently controlled in prevalent hemodialysis patients. Ther Apher Dial. 2013;17(2):221-228. doi: https://doi.org/10.1111/1744-9987.12030Taniguchi M, Fukagawa M, Fujii N, et al. Serum phosphate and calcium should be primarily and consistently controlled in prevalent hemodialysis patients. Ther Apher Dial. 2013;17(2):221-228. doi: https://doi.org/10.1111/1744-9987.12030Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients. J Am Coll Cardiol. 2002;39(4):695-701. doi: https://doi.org/10.1016/s0735-1097(01)01781-8Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients. J Am Coll Cardiol. 2002;39(4):695-701. doi: https://doi.org/10.1016/s0735-1097(01)01781-8Tentori F, McCullough K, Kilpatrick RD, et al. High rates of death and hospitalization follow bone fracture among hemodialysis patients. Kidney Int. 2014;85(1):166-173. doi: https://doi.org/10.1038/ki.2013.279Tentori F, McCullough K, Kilpatrick RD, et al. High rates of death and hospitalization follow bone fracture among hemodialysis patients. Kidney Int. 2014;85(1):166-173. doi: https://doi.org/10.1038/ki.2013.279Hofer AM, Brown EM. Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol. 2003;4(7):530-538. doi: https://doi.org/10.1038/nrm1154Hofer AM, Brown EM. Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol. 2003;4(7):530-538. doi: https://doi.org/10.1038/nrm1154Lindberg JS. Calcimimetics: a new tool for management of hyperparathyroidism and renal osteodystrophy in patients with chronic kidney disease. Kidney Int Suppl. 2005(95):S33-36. doi: https://doi.org/10.1111/j.1523-1755.2005.09505.xLindberg JS. Calcimimetics: a new tool for management of hyperparathyroidism and renal osteodystrophy in patients with chronic kidney disease. Kidney Int Suppl. 2005(95):S33-36. doi: https://doi.org/10.1111/j.1523-1755.2005.09505.xDorsch O. Use of cinacalcet in a patient on long-term dialysis with end-stage renal failure and refractory secondary hyperparathyroidism. Nephrol Dial Transplant. 2007;22(2):637-640. doi: https://doi.org/10.1093/ndt/gfl547Dorsch O. Use of cinacalcet in a patient on long-term dialysis with end-stage renal failure and refractory secondary hyperparathyroidism. Nephrol Dial Transplant. 2007;22(2):637-640. doi: https://doi.org/10.1093/ndt/gfl547Nemeth EF, Heaton WH, Miller M, et al. Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. J Pharmacol Exp Ther. 2004;308(2):627-635. doi: https://doi.org/10.1124/jpet.103.057273Nemeth EF, Heaton WH, Miller M, et al. Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. J Pharmacol Exp Ther. 2004;308(2):627-635. doi: https://doi.org/10.1124/jpet.103.057273Tominaga 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. doi: https://doi.org/10.1111/1744-9987.12352Tominaga 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. doi: https://doi.org/10.1111/1744-9987.12352Егшатян Л.В. Эффективность терапевтического и хирургического лечения вторичного гиперпаратиреоза у пациентов, получающих заместительную почечную терапию программным гемодиализом: Дис. … канд. мед. наук. — М.; 2012. [Egshatyan LV. Effektivnost’ terapevticheskogo i khirurgicheskogo lecheniya vtorichnogo giperparatireoza u patsientov, poluchayushchikh zamestitel’nuyu pochechnuyu terapiyu programmnym gemodializom. [dissertation] Moscow; 2012. (In Russ.)]Егшатян Л.В. Эффективность терапевтического и хирургического лечения вторичного гиперпаратиреоза у пациентов, получающих заместительную почечную терапию программным гемодиализом: Дис. … канд. мед. наук. — М.; 2012. [Egshatyan LV. Effektivnost’ terapevticheskogo i khirurgicheskogo lecheniya vtorichnogo giperparatireoza u patsientov, poluchayushchikh zamestitel’nuyu pochechnuyu terapiyu programmnym gemodializom. [dissertation] Moscow; 2012. (In Russ.)]Nakashima D, Takama H, Ogasawara Y, et al. Effect of cinacalcet hydrochloride, a new calcimimetic agent, on the pharmacokinetics of dextromethorphan: in vitro and clinical studies. J Clin Pharmacol. 2007;47(10):1311-1319. doi: https://doi.org/10.1177/0091270007304103Nakashima D, Takama H, Ogasawara Y, et al. Effect of cinacalcet hydrochloride, a new calcimimetic agent, on the pharmacokinetics of dextromethorphan: in vitro and clinical studies. J Clin Pharmacol. 2007;47(10):1311-1319. doi: https://doi.org/10.1177/0091270007304103Kiefer L, Leiris S, Dodd RH. Novel calcium sensing receptor ligands: a patent survey. Expert Opin Ther Pat. 2011;21(5):681-698. doi: https://doi.org/10.1517/13543776.2011.568479Kiefer L, Leiris S, Dodd RH. Novel calcium sensing receptor ligands: a patent survey. Expert Opin Ther Pat. 2011;21(5):681-698. doi: https://doi.org/10.1517/13543776.2011.568479Walter 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. doi: /https://doi.org/10.1124/jpet.113.204834Walter 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. doi: /https://doi.org/10.1124/jpet.113.204834Block GA, Bushinsky DA, 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. doi: https://doi.org/10.1001/jama.2016.19468Block GA, Bushinsky DA, 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. doi: https://doi.org/10.1001/jama.2016.19468Kawata T, Tokunaga S, Murai M, et al. A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro. PLoS One. 2018;13(4):e0195316. doi: https://doi.org/10.1371/journal.pone.0195316Kawata T, Tokunaga S, Murai M, et al. A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro. PLoS One. 2018;13(4):e0195316. doi: https://doi.org/10.1371/journal.pone.0195316Palmer SC, Nistor I, Craig JC, et al. Cinacalcet in patients with chronic kidney disease: a cumulative meta-analysis of randomized controlled trials. PLoS Med. 2013;10(4):e1001436. doi: https://doi.org/10.1371/journal.pmed.1001436Palmer SC, Nistor I, Craig JC, et al. Cinacalcet in patients with chronic kidney disease: a cumulative meta-analysis of randomized controlled trials. PLoS Med. 2013;10(4):e1001436. doi: https://doi.org/10.1371/journal.pmed.1001436Fukumoto K, Noguchi T, Toriie S, et al. The mechanism of upper-gastrointestinal complication after taking cinacalcet hydrochloride. J Jpn Soc Dial Ther. 2010;43:309-315.Fukumoto K, Noguchi T, Toriie S, et al. The mechanism of upper-gastrointestinal complication after taking cinacalcet hydrochloride. J Jpn Soc Dial Ther. 2010;43:309-315.Sassi G, Striano B, Merlo UA. A reporting system for the assessment of chemotherapy toxicity. J Oncol Pharm Pract. 2005;11(2):63-67. doi: https://doi.org/10.1191/1078155205jp154oaSassi G, Striano B, Merlo UA. A reporting system for the assessment of chemotherapy toxicity. J Oncol Pharm Pract. 2005;11(2):63-67. doi: https://doi.org/10.1191/1078155205jp154oaBoussios S, Pentheroudakis G, Katsanos K, Pavlidis N. Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management. Ann Gastroenterol. 2012;25(2):106-118.Boussios S, Pentheroudakis G, Katsanos K, Pavlidis N. Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management. Ann Gastroenterol. 2012;25(2):106-118.Yokoyama K, Shimazaki R, Fukagawa M, et al. Long-Term Efficacy and Safety of Evocalcet in Japanese Patients with Secondary Hyperparathyroidism Receiving Hemodialysis. Sci Rep. 2019;9(1):6410. doi: https://doi.org/10.1038/s41598-019-42017-zYokoyama K, Shimazaki R, Fukagawa M, et al. Long-Term Efficacy and Safety of Evocalcet in Japanese Patients with Secondary Hyperparathyroidism Receiving Hemodialysis. Sci Rep. 2019;9(1):6410. doi: https://doi.org/10.1038/s41598-019-42017-zAkizawa T, Shimazaki R, Fukagawa M, Evocalcet Study G. Phase 2b study of evocalcet (KHK7580), a novel calcimimetic, in Japanese patients with secondary hyperparathyroidism undergoing hemodialysis: A randomized, double-blind, placebo-controlled, dose-finding study. PLoS One. 2018;13(10):e0204896. doi: https://doi.org/ 10.1371/journal.pone.0204896Akizawa T, Shimazaki R, Fukagawa M, Evocalcet Study G. Phase 2b study of evocalcet (KHK7580), a novel calcimimetic, in Japanese patients with secondary hyperparathyroidism undergoing hemodialysis: A randomized, double-blind, placebo-controlled, dose-finding study. PLoS One. 2018;13(10):e0204896. doi: https://doi.org/ 10.1371/journal.pone.0204896Tsuruya K, Shimazaki R, Fukagawa M, Akizawa T. Efficacy and safety of evocalcet in Japanese peritoneal dialysis patients. Clin Exp Nephrol. 2019;23(6):739-748. doi: https://doi.org/ 10.1007/s10157-019-01692-y.Tsuruya K, Shimazaki R, Fukagawa M, Akizawa T. Efficacy and safety of evocalcet in Japanese peritoneal dialysis patients. Clin Exp Nephrol. 2019;23(6):739-748. doi: https://doi.org/ 10.1007/s10157-019-01692-y.

The authors declare that there are no conflicts of interest present.