A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.

Takehisa Kawata,Masafumi Fukagawa,Waka Haruyama,Nami Masuda,Hiroshi Miyazaki,Yutaka Hisada,Tetsuya Yanagida,Youji Shoukei,Shin Tokunaga,Miki Murai,Tadao Akizawa,Michihito Wada,Dengshun Miao

doi:10.1371/journal.pone.0195316

Takehisa Kawata, Masafumi Fukagawa + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0195316

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Journal: PloS one	Publication Date: Apr 3, 2018
Citations: 53	License type: CC BY 4.0

Affiliation: Kyowa Kirin (Japan), Tokai University, Showa University

Abstract

Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin.

Highlights

Secondary hyperparathyroidism (SHPT), characterized by the elevation of serum parathyroid hormone (PTH) levels, is a common disorder in patients with chronic kidney disease (CKD), especially those on renal replacement therapy [1]
As CKD progresses, an extreme increase in the serum PTH levels results in high-turnover bone disease and increases the serum calcium and phosphate levels. Such abnormal mineral metabolism often results in vascular calcification, fracture, and an increased risk of all-cause and cardiovascular mortality [2,3,4,5]
The stimulation of calcium receptor (CaR) induces the intracellular release of calcium from cytoplasmic Ca stores

Summary

Introduction

Secondary hyperparathyroidism (SHPT), characterized by the elevation of serum parathyroid hormone (PTH) levels, is a common disorder in patients with chronic kidney disease (CKD), especially those on renal replacement therapy [1]. As CKD progresses, an extreme increase in the serum PTH levels results in high-turnover bone disease and increases the serum calcium and phosphate levels. Such abnormal mineral metabolism often results in vascular calcification, fracture, and an increased risk of all-cause and cardiovascular mortality [2,3,4,5]. Cinacalcet has been widely used to manage SHPT in dialysis patients [8,9,10,11,12,13], and is associated with a reduced risk of cardiovascular calcification, hospitalization and heart failure [14,15,16]. Cinacalcet has helped to drastically reduce the number of parathyroidectomy (PTx) surgeries [17]

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