A novel calcimimetic evocalcet for the management of secondary hyperparathyroidism with little effect on the gastrointestinal tract and cyp isozymes in vivo and in vitro

In the treatment of secondary hyperparathyroidism of end-stage chronic kidney disease, vitamin D receptor activation and allosteric modulators of the calcium-sensing receptor - inhibit glandular hyperplasia; reduce parathyroid hormone levels, impact on bone turnover and mineral density. Cinacalcet, an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism in chronic kidney disease. Nevertheless, some patients remain refractory to the treatment, as the dose of cinacalcet cannot be sufficiently increased due to gastrointestinal symptoms and it strong inhibits of cytochrome P450 (CYP) 2D6. In order to resolve this issue, was develop a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of chronic kidney disease induced by 5/6 nephrectomy, and in multicenter, open-label study phase 3, and in clinical practice oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone. Evocalcet also demonstrated the less induction of emesis and gastro-intestinal effects, and its pharmacological effects were observed at lower doses because of its higher bioavailability than cinacalcet. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro. These findings suggest that evocalcet can be a better alternative to cinacalcet with a wider safety margin

The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases

The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and β-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers

A novel calcimimetic evocalcet for the management of secondary hyperparathyroidism with little effect on the gastrointestinal tract and cyp isozymes in vivo and in vitro

In the treatment of secondary hyperparathyroidism of end-stage chronic kidney disease, vitamin D receptor activation and allosteric modulators of the calcium-sensing receptor - inhibit glandular hyperplasia; reduce parathyroid hormone levels, impact on bone turnover and mineral density. Cinacalcet, an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism in chronic kidney disease. Nevertheless, some patients remain refractory to the treatment, as the dose of cinacalcet cannot be sufficiently increased due to gastrointestinal symptoms and it strong inhibits of cytochrome P450 (CYP) 2D6. In order to resolve this issue, was develop a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of chronic kidney disease induced by 5/6 nephrectomy, and in multicenter, open-label study phase 3, and in clinical practice oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone. Evocalcet also demonstrated the less induction of emesis and gastro-intestinal effects, and its pharmacological effects were observed at lower doses because of its higher bioavailability than cinacalcet. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro. These findings suggest that evocalcet can be a better alternative to cinacalcet with a wider safety margin.</jats:p