First-in-Patient Phase I/II Study of Upacicalcet in Japanese Patients with Secondary Hyperparathyroidism Undergoing Hemodialysis: Pharmacokinetic and Pharmacodynamic Properties,Clinical Pharmacokinetics

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First-in-Patient Phase I/II Study of Upacicalcet in Japanese Patients with Secondary Hyperparathyroidism Undergoing Hemodialysis: Pharmacokinetic and Pharmacodynamic Properties
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-06-28 , DOI: 10.1007/s40262-022-01139-w
Junichiro James Kazama ₁ , Fumihiko Koiwa ₂ , Keitaro Yokoyama ₃ , Masafumi Fukagawa ₄ , Kenji Asano ₅ , Daisuke Honda ₆ , Tadao Akizawa ₇

Affiliation

Objective

Upacicalcet is a new renally excreted and injectable calcimimetic agent. We evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of single and multiple intravenous administration of upacicalcet in patients with secondary hyperparathyroidism undergoing hemodialysis.

Methods

This study was a multicenter, randomized, placebo-controlled, double-blinded, dose-escalation study consisting of a single-dose study and a multiple-dose study. The single-dose study consisted of seven dose steps from 0.025 to 0.8 mg. For each step, six patients were randomly assigned 2:1 to receive upacicalcet or a placebo. The multiple-dose study occurred over 3 weeks in three-dose steps from 0.05 to 0.2 mg. For each step, 12 patients were randomly assigned 3:1 to receive upacicalcet or a placebo.

Results

The plasma concentration of upacicalcet increased in a dose-dependent manner and was maintained for the next dialysis. Upacicalcet was approximately 80% removed by a single dialysis and did not increase in the plasma concentration with repeated administration. Serum intact parathyroid hormone and corrected calcium (Ca²⁺) levels tended to decrease in response to the plasma concentration of upacicalcet. In the single-dose study, upper gastrointestinal symptoms were observed as a non-serious and mild adverse drug reaction in the groups receiving upacicalcet ≥ 0.4 mg. In the multiple-dose study, abdominal discomfort occurred in each patient in the 0.1 mg and 0.2 mg groups.

Conclusions

Upacicalcet for patients with secondary hyperparathyroidism undergoing hemodialysis could be a calcimimetic agent that acts in a dose-dependent manner and persistently until the next dialysis session. No safety or tolerability issues specific to upacicalcet were found.

中文翻译：

在接受血液透析的日本继发性甲状旁腺功能亢进患者中 Upacicalcet 的首次患者 I/II 期研究：药代动力学和药效学特性

客观的

Upacicalcet 是一种新的肾脏排泄和可注射的拟钙剂。我们评估了接受血液透析的继发性甲状旁腺功能亢进患者单次和多次静脉注射upacicalcet的药代动力学、药效学、安全性和耐受性。

方法

本研究是一项多中心、随机、安慰剂对照、双盲、剂量递增研究，包括单剂量研究和多剂量研究。单剂量研究包括从 0.025 到 0.8 mg 的七个剂量步骤。对于每一步，六名患者被随机分配 2:1 接受 upacicalcet 或安慰剂。多剂量研究在 3 周内以 0.05 至 0.2 毫克的三剂量步骤进行。对于每一步，12 名患者被随机分配 3:1 接受 upacicalcet 或安慰剂。

结果

upacicalcet 的血浆浓度以剂量依赖性方式增加，并在下一次透析时保持不变。Upacicalcet 通过单次透析去除约 80%，并且在重复给药时血浆浓度没有增加。血清完整的甲状旁腺激素和校正的钙（Ca ²⁺）水平随着upacicalcet的血浆浓度而降低。在单剂量研究中，在接受 upacicalcet ≥ 0.4 mg 的组中，上消化道症状被观察为非严重和轻度的药物不良反应。在多剂量研究中，0.1 mg 和 0.2 mg 组的每位患者均出现腹部不适。