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

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 hyperpho...

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Bibliographic Details
Published in:PloS one 2018-04, Vol.13 (4), p.e0195316-e0195316
Main Authors: Kawata, Takehisa, Tokunaga, Shin, Murai, Miki, Masuda, Nami, Haruyama, Waka, Shoukei, Youji, Hisada, Yutaka, Yanagida, Tetsuya, Miyazaki, Hiroshi, Wada, Michihito, Akizawa, Tadao, Fukagawa, Masafumi
Format: Article
Language:English
Subjects:
Bioavailability
Biology and life sciences
Calcification
Calcimimetics
Care and treatment
Cytochrome
Cytochrome P450
Development and progression
Disease control
Gastric emptying
Gastrointestinal symptoms
Gastrointestinal tract
Health aspects
Hemodialysis
Hypercalcemia
Hyperparathyroidism
Hyperphosphatemia
Intestine
Isoenzymes
Kidney diseases
Laboratories
Liver
Medicine and Health Sciences
Metabolism
Motility
Nephrectomy
Nephrology
Oral administration
Parathyroid
Parathyroid hormone
Pharmacology
Properties
R&D
Research & development
Research and Analysis Methods
Rodents
Safety margins
Secretion
Vitamin D
Vomiting
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0195316