Drug Insight: Renal Indications of Calcimimetics
Drug Insight: Renal Indications of Calcimimetics
Calcimimetics suppress the secretion of parathyroid hormone by sensitizing the parathyroid calcium receptor to serum calcium. Cinacalcet (Sensipar/Mimpara, Amgen Inc., Thousand Oaks, CA), the first-in-class calcimimetic agent approved for treatment of secondary hyperparathyroidism in dialysis patients, is, in association with higher dose of a calcium-based oral phosphate binder, a well-tolerated and effective alternative to standard treatments such as vitamin D derivatives in association with a non-calcium-based oral phosphate binder. Here, we present an overview of evidence in support of this assertion. We extend our discussion to encompass other indications for calcimimetics—secondary hyperparathyroidism in predialysis chronic kidney disease patients, hypercalcemic hyperparathyroidism in renal transplant recipients, primary hyperparathyroidism, and hypercalcemia associated with parathyroid carcinoma—as well as providing guidance on optimal usage of this drug.
Calcimimetics suppress secretion of parathyroid hormone (PTH) by increasing the sensitivity of the calcium receptors of parathyroid cells to extracellular ionized calcium. As the activity of drugs of this class is dependent upon calcium-induced spatial modification of its receptor, it would be more appropriate to refer to them as 'positive allosteric modulators'; however, popular usage has established their name as 'calcimimetics'.
The development of calcimimetics is an example of intelligent drug design and its rapid translation into a useful drug. The discovery by Brown in 1993 that the calcium-sensing protein was a G-protein-coupled receptor came as a surprise. At the time, no small cation was known to act as a ligand in this receptor family. It is now accepted that serum calcium binds to the extracellular portion of the calcium-sensing receptor and activates a cascade of intracellular signals (such as the release of intracellular calcium, protein kinase C and phosphoinositides) that in turn suppress the secretion of PTH, resulting in a decreased concentration of serum calcium.
The calcimimetic prototype NPS-R568 was efficacious in primary and secondary hyperparathyroidism and in parathyroid carcinoma; however, the unpredictable pharmacokinetics of this compound led to its being replaced by cinacalcet hydrochloride (HCl). Cinacalcet HCl was recently approved by the US FDA and European Medicines Agency for treatment of secondary hyperparathyroidism of dialysis patients and parathyroid carcinoma. Manufactured by Amgen, cinacalcet HCl is marketed as Sensipar (Amgen Inc., Thousand Oaks, CA) in the US and as Mimpara (Amgen Inc.) in Europe. (See Box 1 for a list of clinically relevant pharmacokinetic interactions.)
Summary and Introduction
Summary
Calcimimetics suppress the secretion of parathyroid hormone by sensitizing the parathyroid calcium receptor to serum calcium. Cinacalcet (Sensipar/Mimpara, Amgen Inc., Thousand Oaks, CA), the first-in-class calcimimetic agent approved for treatment of secondary hyperparathyroidism in dialysis patients, is, in association with higher dose of a calcium-based oral phosphate binder, a well-tolerated and effective alternative to standard treatments such as vitamin D derivatives in association with a non-calcium-based oral phosphate binder. Here, we present an overview of evidence in support of this assertion. We extend our discussion to encompass other indications for calcimimetics—secondary hyperparathyroidism in predialysis chronic kidney disease patients, hypercalcemic hyperparathyroidism in renal transplant recipients, primary hyperparathyroidism, and hypercalcemia associated with parathyroid carcinoma—as well as providing guidance on optimal usage of this drug.
Introduction
Calcimimetics suppress secretion of parathyroid hormone (PTH) by increasing the sensitivity of the calcium receptors of parathyroid cells to extracellular ionized calcium. As the activity of drugs of this class is dependent upon calcium-induced spatial modification of its receptor, it would be more appropriate to refer to them as 'positive allosteric modulators'; however, popular usage has established their name as 'calcimimetics'.
The development of calcimimetics is an example of intelligent drug design and its rapid translation into a useful drug. The discovery by Brown in 1993 that the calcium-sensing protein was a G-protein-coupled receptor came as a surprise. At the time, no small cation was known to act as a ligand in this receptor family. It is now accepted that serum calcium binds to the extracellular portion of the calcium-sensing receptor and activates a cascade of intracellular signals (such as the release of intracellular calcium, protein kinase C and phosphoinositides) that in turn suppress the secretion of PTH, resulting in a decreased concentration of serum calcium.
The calcimimetic prototype NPS-R568 was efficacious in primary and secondary hyperparathyroidism and in parathyroid carcinoma; however, the unpredictable pharmacokinetics of this compound led to its being replaced by cinacalcet hydrochloride (HCl). Cinacalcet HCl was recently approved by the US FDA and European Medicines Agency for treatment of secondary hyperparathyroidism of dialysis patients and parathyroid carcinoma. Manufactured by Amgen, cinacalcet HCl is marketed as Sensipar (Amgen Inc., Thousand Oaks, CA) in the US and as Mimpara (Amgen Inc.) in Europe. (See Box 1 for a list of clinically relevant pharmacokinetic interactions.)
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