Negri Armando L, Bover Jordi, Vervloet Marc, Cozzolino Mario
Nephrology Section, Instituto de Investigaciones Metabólicas, Universidad del Salvador, Libertad 836 1 Floor, Buenos Aires, Argentina.
Department of Nephrology, University Hospital Germans Trias i Pujol, Badalona, Spain.
J Nephrol. 2025 Mar;38(2):415-421. doi: 10.1007/s40620-024-02119-y. Epub 2024 Oct 15.
Secondary hyperparathyroidism is one of the most frequent metabolic abnormalities found in patients with chronic kidney disease. The calcium-sensing receptor senses extracellular calcium and is the principal regulator of parathyroid hormone secretion. Cloning of the calcium-sensing receptor led to the development of calcimimetics, drugs that decrease parathyroid hormone secretion through the positive allosteric modulation of this receptor. Cinacalcet was the first oral calcimimetic approved by the US Food and Drug Administration (FDA) in 2004 for the treatment of secondary hyperparathyroidism in adult patients on dialysis. Although cinacalcet has demonstrated safety and effectiveness, it has two main problems: gastrointestinal side effects that result in poor adherence, and the inhibitory action on CYP2D6 with the possibility of interactions with commonly used medications. To address the problem of oral compliance, Etelcalcetide, a small synthetic polycationic peptide IV calcimimetic was introduced in 2017. This drug showed a 10% greater decrease in serum parathyroid hormone values compared to cinacalcet but no better gastrointestinal tolerance, with greater risk of hypocalcemia. Several structural modifications were introduced in cinacalcet to produce a new compound called evocalcet. This drug, which was introduced in Japan in 2018, has considerably enhanced bioavailability and decreased both the inhibitory effect on CYP2D6 and half of the gastrointestinal side effects of cinacalcet. Finally, a novel non-peptidic injectable calcimimetic agent, upacicalcet, became available in Japan in 2021. This agent has greater clearance by hemodialysis and shows no effect on gastric emptying. More studies are needed comparing the old calcimimetics to the new ones to establish their future role in the treatment of secondary hyperparathyroidism in chronic kidney disease (CKD) G5D.
继发性甲状旁腺功能亢进是慢性肾脏病患者中最常见的代谢异常之一。钙敏感受体可感知细胞外钙，是甲状旁腺激素分泌的主要调节因子。钙敏感受体的克隆促使了拟钙剂的研发，这类药物通过对该受体的正构变构调节来减少甲状旁腺激素的分泌。西那卡塞是2004年美国食品药品监督管理局（FDA）批准的首个用于治疗成年透析患者继发性甲状旁腺功能亢进的口服拟钙剂。尽管西那卡塞已证明其安全性和有效性，但它有两个主要问题：导致依从性差的胃肠道副作用，以及对CYP2D6的抑制作用，可能与常用药物发生相互作用。为了解决口服依从性问题，2017年引入了依特卡肽，一种小型合成聚阳离子肽静脉注射拟钙剂。与西那卡塞相比，该药物使血清甲状旁腺激素值降低了10%，但胃肠道耐受性并无改善，且低钙血症风险更高。西那卡塞经过了几次结构修饰，产生了一种名为埃沃卡塞的新化合物。这种药物于2018年在日本推出，其生物利用度显著提高，对CYP2D6的抑制作用以及西那卡塞胃肠道副作用的一半均有所降低。最后，一种新型非肽类注射用拟钙剂乌帕卡塞于2021年在日本上市。该药物通过血液透析的清除率更高，且对胃排空无影响。需要进行更多研究，比较旧的拟钙剂和新的拟钙剂，以确定它们在慢性肾脏病（CKD）G5D患者继发性甲状旁腺功能亢进治疗中的未来作用。
