First-in-Human Phase I Study of the Novel Injectable Calcimimetic Agent Upacicalcet in Healthy Adult Japanese Participants

Abstract

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.

Comparative effects of calcitriol and calcimimetic on bone health in renal insufficiency

“…The phase I trials of calcimimetics, carried out in healthy subjects, were intended to assess pharmacokinetics, pharmacodynamics, safety, tolerability, and the efficacy of oral and intravenous molecules on the levels of PTH and other factors involved in the phosphate and calcium metabolism. However, no effects in bone were reported in these preliminary studies 50–54 . With regard to vitamin D, and also in the context of primary hyperparathyroidism without CKD, it has been documented a decreased bone turnover due to vitamin D‐mediated inhibition of PTH secretion 55,56 .…”

“…However, no effects in bone were reported in these preliminary studies. [50][51][52][53][54] With regard to vitamin D, and also in the context of primary hyperparathyroidism without CKD, it has been documented a decreased bone turnover due to vitamin D-mediated inhibition of PTH secretion. 55,56 The administration of vitamin D has been also reported in osteoporosis.…”

Efficacy and Safety of Upacicalcet in Hemodialysis Patients with Secondary Hyperparathyroidism

“…Phase 1 and 2 clinical trials showed that its interdialytic plasma half-life was 65–122 hours in HD patients, which is markedly longer than that in healthy participants. 19,20 Moreover, its removal rate in a HD session was 79%–100%. Therefore, the plasma concentration of upacicalcet plateaus after 1 week of administration after each dialysis session, contrary to etelcalcetide.…”