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

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.

Assessment of CYP‐Mediated Drug Interactions for Evocalcet, a New Calcimimetic Agent, Based on In Vitro Investigations and a Cocktail Study in Humans

“…The in vitro method used to characterize the direct inhibitory effects of evocalcet on the specific activities of nine CYP isozymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) was described previously …”

“…Evocalcet (MT‐4580/KHK7580) is a new calcimimetic agent with a dose‐dependent PTH‐lowering effect that only marginally affected gastric emptying in a nonclinical study . Noninferiority of evocalcet to cinacalcet for suppression of intact PTH, with fewer GI‐related adverse events (AEs), was demonstrated in a randomized clinical trial of patients with SHPT undergoing hemodialysis .…”

“…The US Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency guidelines recommend that the potential for DDIs in new drugs should be assessed in vitro and in vivo . Evocalcet did not cause reversible inhibition of eight CYP isozymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A) within the concentration range of 0.15–50 μmol/L in vitro . Evocalcet was shown to competitively inhibit CYP2D6‐specific metabolic activity, with 50.7% residual activity at the maximum tested evocalcet concentration of 50 μmol/L.…”

Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment

“…Cinacalcet, a calcimimetic agent that suppresses PTH by direct action on the parathyroid CaSR, was approved in western countries in 2004 and in Japan in 2008 . A second calcimimetic, an intravenous formulation of etelcalcetide (February 2017) , and a third, evocalcet (May 2018) became clinically available in Japan ahead of all other countries. At the same time, the importance of P control has been recognized for mortality, cardiovascular calcification, and SHPT outcomes, which has led to development of phosphate binders (Fig.…”

“…A new oral calcimimetic, evocalcet (65)(66)(67)(68)(69), has also been developed and was approved in Japan in April 2018. In a controlled trial with cinacalcet, evocalcet had noninferiority for PTH inhibition.…”