Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism.

BACKGROUND: Adequate control of all four KDOQI biochemical targets for chronic kidney disease, bone and mineral disorder (CKD-MBD), which include parathyroid hormone (PTH), calcium (Ca), phosphorus (P) and Ca x P, remains difficult and is accomplished in <6% of patients receiving haemodialysis. The objective of the current study was to determine whether treatment with cinacalcet combined with low doses of vitamin D sterols improves control of both PTH and Ca x P among haemodialysis patients with secondary hyperparathyroidism (sHPT). METHODS: This multicentre, open-label study enrolled haemodialysis subjects (N = 444) with moderate to severe sHPT (mean serum biPTH > 160-430 pg/mL) (approximately iPTH 300-800 pg/mL or ng/L). Cinacalcet was titrated sequentially (30-180 mg/day) during an 8-week dose-titration phase to achieve biPTH

First- and second-generation immunometric PTH assays during treatment of hyperparathyroidism with cinacalcet HCl.

BACKGROUND: First-generation immunometric assays for "intact" parathyroid hormone (iPTH) also measure large N-terminally truncated PTH fragments, whereas second-generation assays, such as the "bio-intact" PTH (biPTH) assay, measure only full-length biologically active PTH(1-84). This study compared iPTH and biPTH assays during cinacalcet treatment in subjects with secondary HPT receiving dialysis. METHODS: Four hundred and ten subjects were enrolled in a 26-week randomized, double-blind, placebo-controlled trial of oral cinacalcet (or placebo), 30 to 180 mg once daily, and efficacy was assessed using biPTH and iPTH assays. RESULTS: Compared with control treatment, cinacalcet improved the management of secondary HPT. Both biPTH and iPTH decreased by 38%+/- 3% during weeks 13 to 26 in the cinacalcet group; biPTH increased by 23%+/- 4% and iPTH increased by 9.5%+/- 3% in the control group (P < 0.001). Fifty-six percent of cinacalcet subjects and 10% of control subjects had a > or = 30% reduction in biPTH, and 61% and 11%, respectively, had a > or = 30% reduction in iPTH. Significant correlations between biPTH and iPTH levels were observed throughout the study. Both assays correlated similarly with bone-specific alkaline phosphatase levels. The ratio of biPTH to iPTH was maintained at 56% +/- 1% after treatment in both treatment groups. Increasing serum calcium levels were associated with a decreasing ratio of biPTH to (iPTH-biPTH). CONCLUSION: These data show that PTH can be monitored with either iPTH or biPTH assays during therapy with cinacalcet, and that cinacalcet therapy does not exert a major influence on the ratio between PTH(1-84) and large, N-terminally truncated PTH fragments.

Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl.

BACKGROUND: The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQItrade mark) has established guidelines for treatment of secondary hyperparathyroidism (HPT). The ability of cinacalcet HCl (Sensipartrade mark) treatment to improve achievement of target levels of parathyroid hormone (PTH), calcium, phosphorus, and calcium-phosphorus product (Ca x P) was investigated in subjects on dialysis with secondary HPT. METHODS: Data were combined from three placebo-controlled, double-blind, 26-week studies with similar design that randomized 1136 subjects on dialysis to receive traditional therapy plus cinacalcet or placebo. Oral cinacalcet was titrated from 30 to 180 mg/day. Achievement of K/DOQI goals was determined for each treatment group overall and for subgroups defined by baseline intact PTH (iPTH) and Ca x P levels. RESULTS: Cinacalcet-treated subjects were more likely to achieve a mean iPTH

Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.

The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease.

Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treatment of hyperparathyroidism known as calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, despite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dose-titration study with single daily oral doses of AMG 073/placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium x phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P = 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH < or = 250 pg/ml compared with placebo patients (20%; P = 0.029). Also, a significantly greater proportion of AMG 073 patients (53%) had a decrease in PTH > or =30% compared with placebo patients (23%; P = 0.009). Calcium x phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P = 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium x phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.

The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism.

BACKGROUND: A need exists for a therapy that lowers parathyroid hormone (PTH) without increasing calcium x phosphorus in patients with secondary hyperparathyroidism. The calcimimetic AMG 073 increases the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium, thereby reducing PTH secretion. Consequently, AMG 073 may provide a novel therapy for secondary hyperparathyroidism. METHODS: Seventy-eight hemodialysis patients with secondary hyperparathyroidism were enrolled into this 18-week, double-blind, randomized, placebo-controlled, dose titration study. Daily oral AMG 073 doses were administered to determine the effect on PTH, serum calcium, phosphorus, and calcium x phosphorus. RESULTS: The mean baseline PTH was similar in patients administered AMG 073 or placebo (632 +/- 280.1 pg/mL vs. 637 +/- 455.9 pg/mL, respectively). PTH decreased by 26.0% in the AMG 073-treated group, compared with an increase of 22.0% in the placebo group (P < 0.001). A greater proportion in the AMG 073 group (38%) had a decrease in PTH >or=30%, compared with the placebo group (8%) (P = 0.001). Decreases in PTH were independent of baseline vitamin D usage. Patients receiving AMG 073 had an 11.9% decrease in calcium x phosphorus compared with a 10.9% increase in the placebo group (P < 0.001). Use of vitamin D sterols, as well as both calcium and noncalcium-containing phosphate binders. were similar between treatment groups. Administration of AMG 073 was safe and well tolerated in this 18-week study. CONCLUSIONS: The calcimimetic AMG 073 decreases both PTH and calcium x phosphorus levels in hemodialysis patients with secondary hyperparathyroidism.