Background and Objective

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.

Method

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.

Result

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.

Conclusion

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.

中文翻译：

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新型可注射拟钙剂 Upacicalcet 在健康成人日本参与者中的首次人体 I 期研究

背景与目的

Upacicalcet sodium hydrate 是一种新型的小分子拟钙剂，具有治疗继发性甲状旁腺功能亢进症的潜力。我们评估了日本健康成人单次静脉注射乌帕卡塞的药代动力学、药效学、安全性和耐受性。

方法

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注射安慰剂或 0.01、0.1、1.0 或 2.5 mg 的 upacicalcet。

结果

upacicalcet的血浆浓度以剂量依赖性方式增加。Upacicalcet 给药后迅速从血浆中消失。upacicalcet 的半衰期约为 1-2 小时。upacicalcet的主要排泄途径是通过尿液。血清完整的甲状旁腺激素随着upacicalcet的剂量从0.01 mg的最低剂量开始下降。1.0 mg 组 1 例患者和 2.5 mg 组 5 例患者出现胃肠道疾病。所有不良事件均不严重，未发生症状性低钙血症。

结论

这项研究表明，upacicalcet 可作为拟钙剂，以原形从尿中排出，几乎没有新陈代谢。此外，upacicalcet 是一种小分子，分布容积小。此外，不到 50% 的 upacicalcet 与人血浆蛋白结合。这些发现表明，对接受血液透析的患者给药的upacicalcet可能具有较长的排泄期和持续的药理作用。