Hyperparathyroidism – cinacalcet
Parathyroid hormone plays an essential role in controlling the distribution of calcium and phosphate around the body. Elevated parathyroid hormone levels can lead to osteoporosis. Overproduction of the hormone is often a result of one of the four parathyroid glands malfunctioning. Calcimimetic drugs have been developed for patients with a mild form of the disease, or those whose condition is secondary in origin.
Calcimimetics act at the extracellular calcium sensing receptor, or CaR, which is a low affinity G-protein coupled receptor that can be activated by small changes in extracellular calcium. The receptor is not very specific, and can be activated by several other ions such as magnesium; its activation is involved in the control of calcium homeostasis in the body. Calcimimetic drugs enhance the parathyroid cell receptors' affinity for calcium, hence decreasing their secretion of the hormone.
Cinacalcet hydrochloride, formerly known as AMG-073, is being developed as a treatment for both primary and secondary hyperparathyroidism. Discovered by Allelix and licensed to Amgen and Kirin Brewery, it has a higher oral bioavailability than R-568, and more consistent pharmacokinetics. Two prospective randomised double blind placebo controlled trials in 78 patients with primery hyperparathyroidism involved a 12-week treatment phase, followed by a maintenance phase of either 12 or 40 weeks. The drug was well tolerated, and after 24 weeks 88% of those receiving the active had their serum calcium levels reduced by at least 0.5mg/dl, compared with 5% of those given placebo.1
For secondary hyperparathyroidism, a total of 52 patients on dialysis with end stage renal disease and secondary hyperparathyroidism were given 5, 10, 25, 50, 75 and 100mg orally, followed by 10, 25 or 50mg/day for eight days. Those given the higher doses experienced a modest drop in calcium levels.2 The combined results of three trials on a total of 215 patients on dialysis showed that 83% of those given cinacalcet experienced a decrease in baseline intact parathyroid hormone of at least 30%.3 Phase III trials of the drug are ongoing.