Division of Nephrology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan.
Sumida Hospital, Souseikai, Tokyo, Japan.
Drugs R D. 2022 Jun;22(2):131-140. doi: 10.1007/s40268-022-00385-4. Epub 2022 Mar 25.
Upacicalcet sodium hydrate is a novel small-molecule calcimimetic and has potential as a therapeutic agent for secondary hyperparathyroidism. We assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of a single intravenous dose of upacicalcet in Japanese healthy adults.
This was a single-center, double-blinded, randomized, placebo-controlled, dose-escalation study. For each cohort, eight subjects were randomly assigned at a ratio of 3:1 to receive a single injection of placebo or upacicalcet 0.01, 0.1, 1.0, or 2.5 mg.
The plasma concentration of upacicalcet increased in a dose-dependent manner. Upacicalcet rapidly disappeared from plasma after administration. The half-life of upacicalcet was approximately 1-2 h. The major excretion route of upacicalcet was via urine. Serum intact parathyroid hormone decreased in accordance with the upacicalcet dose, from the lowest dose of 0.01 mg. Gastrointestinal disorders occurred in one patient in the 1.0 mg group and in five patients in the 2.5 mg group. All adverse events were nonserious, and no symptomatic hypocalcemia occurred.
This study showed that upacicalcet acted as a calcimimetic and was excreted in the urine unchanged with little metabolism. Moreover, upacicalcet is a small molecule and has a small volume of distribution. In addition, less than 50% of upacicalcet binds to human plasma proteins. These findings suggest that upacicalcet administered to patients undergoing hemodialysis might be expected to have a long excretion period and sustained pharmacological effect.
乌帕立钙钠水合物是一种新型小分子钙敏感受体激动剂，有望成为治疗继发性甲状旁腺功能亢进的药物。我们评估了单次静脉给予日本健康成年人乌帕立钙的药代动力学、药效学、安全性和耐受性。
这是一项单中心、双盲、随机、安慰剂对照、剂量递增研究。对于每个队列，8 名受试者以 3:1 的比例随机分配接受单次安慰剂或乌帕立钙 0.01、0.1、1.0 或 2.5 mg 注射。
乌帕立钙的血浆浓度呈剂量依赖性增加。给药后乌帕立钙迅速从血浆中消失。乌帕立钙的半衰期约为 1-2 小时。乌帕立钙的主要排泄途径是尿液。血清全段甲状旁腺激素随着乌帕立钙剂量的降低而降低，最低剂量为 0.01 mg。1.0 mg 组有 1 例患者和 2.5 mg 组有 5 例患者出现胃肠道疾病。所有不良事件均为非严重不良事件，无症状性低钙血症发生。
本研究表明，乌帕立钙作为钙敏感受体激动剂，以原形经尿液排泄，几乎不经代谢，且乌帕立钙为小分子，分布容积小。此外，不到 50%的乌帕立钙与人血浆蛋白结合。这些发现表明，给予血液透析患者乌帕立钙可能具有较长的排泄期和持续的药理作用。
