Future role of calcimimetics in end-stage renal disease

Calcimimetic agents are small organic molecules that act as allosteric activators of the calcium-sensing receptor. In parathyroid cells, they lower the threshold for receptor activation by extracellular calcium ions and diminish parathyroid hormone (PTH) secretion. These compounds offer a novel way of controlling excess PTH secretion in clinical disorders associated with excess PTH secretion, including secondary hyperparathyroidism due to chronic renal failure. The first calcimimetic agent to be evaluated in clinical trials was R-568, but studies were discontinued because of its limited bioavailability and inconsistent pharmacokinetic profile. Extensive assessments are currently underway by using a second-generation calcimimetic compound, AMG 073, to treat secondary hyperparathyroidism. Work completed thus far has shown that AMG 073 effectively lowers plasma PTH, without increasing values for the calcium-phosphorus ion product in serum in patients with end-stage renal disease. Indeed, serum phosphorus levels often decline as plasma PTH levels fall during treatment. Recent experimental evidence also suggests that calcimimetic agents may impede the development of parathyroid gland hyperplasia, an integral component of secondary hyperparathyroidism due to chronic renal failure. Calcimimetics agents have considerable potential therefore as a new approach to the medical management secondary hyperparathyroidism.