Disease relevance of AMG 073

• The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease [1].
• Cinacalcet offers a new therapeutic option for controlling secondary hyperparathyroidism in patients with chronic kidney disease on dialysis [2].
• Bone mineral density was unchanged by cinacalcet, but bone resorption and formation markers increased (P < 0.05) [3].
• CONCLUSION.: Cinacalcet allows the correction of hypercalcemia with no interference in immunosuppressive treatment or renal function [4].
• CONCLUSION: The results confirm previous work demonstrating that calcimimetic agents attenuate the progression of parathyroid hyperplasia in subtotally nephrectomized rats, extending earlier observations to now include cinacalcet HCl [5].
• These data show that medically induced hypoparathyroidism with cinacalcet is a therapeutic option for disorders of FGF-23-mediated hypophosphatemia and that, in the absence of PTH, the phosphaturic effect of FGF-23 is decreased [6].

High impact information on AMG 073

• Once-daily oral cinacalcet was effective in rapidly and safely reducing PTH, Ca x P, calcium, and phosphorus levels in patients who received HD or PD [2].
• 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) [1].
• Cinacalcet chloride is efficient and safe in renal transplant recipients with posttransplant hyperparathyroidism [4].
• Cinacalcet, an allosteric enhancer of the calcium-sensing receptor, is used to treat secondary hyperparathyroidism [7].
• RESULTS: Compared with control treatment, cinacalcet improved the management of secondary HPT [8].

Chemical compound and disease context of AMG 073

• We evaluated the use of the calcimimetic cinacalcet chloride to correct chronic hypercalcemia in posttransplant HPT, in a prospective single-center study [4].
• OBJECTIVE: Cinacalcet (cinacalcet HCl; Sensipar/Mimpara) is a calcimimetic that is a treatment for secondary hyperparathyroidism in patients with renal failure [9].
• Moreover, the introduction of non-calcium-based phosphate binders (sevelamer and lanthanum carbonate) and cinacalcet (an allosteric activator of the calcium receptor that reduces PTH and the serum calciumxphosphate product) may reduce the risk of hypercalcemia with vitamin D therapy [10].
• Normalization of lithium-induced hypercalcemia and hyperparathyroidism with cinacalcet hydrochloride [11].
• Cinacalcet HCl (cinacalcet), a novel calcimimetic compound, restores the sensitivity of the Ca-sensing receptor in parathyroid cells, and decreases serum parathyroid hormone (PTH) without introducing hypercalcemia or hyperphosphatemia [12].

Biological context of AMG 073

• CONCLUSION: The degree of renal impairment and mode of dialysis do not affect the pharmacokinetics or pharmacodynamics of cinacalcet [9].
• There was no difference in apoptosis from cinacalcet HCl-treated or vehicle-treated animals [5].
• Protein binding of cinacalcet, determined in study 1 only, was similar in all groups and the level of renal function did not affect the pharmacodynamics (as determined by intact parathyroid hormone and calcium levels) [9].
• Cinacalcet HCl affected cell proliferation of CHO cells transfected with CaR, dose dependently, but had no effect on human or mouse osteoblastic cell proliferation in calcium-containing medium (1.6 or 8.6 mM) [13].
• During treatment with cinacalcet, total and bone-specific alkaline phosphatase increased, whereas the urinary deoxypyridinoline-creatinine ratio did not change significantly, suggesting enhanced bone formation [14].

Anatomical context of AMG 073

• Calcium (greater than 6.0 mM) inhibited osteoclast formation, but cinacalcet HCl (30-1000 nM) had no effect on osteoclastic formation or resorption in the presence of calcium (1.6 or 6.1 mM) [13].
• Using rat medullary thyroid carcinoma 6-23 cells expressing the CaR, cinacalcet HCl (EC(50) = 34 nM) produced a concentration-dependent increase in calcitonin secretion [15].
• Cinacalcet modulates the calcium-sensing receptor on the parathyroid gland to reduce secretion of parathyroid hormone and lower serum calcium, phosphorus and calcium-phosphorus product in haemodialysis patients [16].

Associations of AMG 073 with other chemical compounds

• However, whether the increased intolerance observed was due to the association of cinacalcet chloride with other drugs required in renal transplantation (e.g., MMF) needs to be assessed [4].
• Notably, cinacalcet HCl proved effective in a broad range of CKD patients on dialysis with uncontrolled secondary HPT, regardless of disease severity, duration of dialysis treatment, dialysis modality, race, age, gender, or concurrent phosphate binder or vitamin D sterol use [17].
• METHODS: Cinacalcet HCl (10 or 1 mg/kg, p.o. gavage), 1,25-dihydroxyvitamin D(3) (0.1 microg, s.c, calcitriol) or the combination was administered daily for 26 days in a rat model of secondary HPT [5/6 nephrectomy] [18].
• Clinical trials have documented that the calcimimetic agent cinacalcet hydrochloride effectively lowers plasma PTH levels without increasing serum calcium or phosphorus concentrations in adult hemodialysis patients with SHPT [19].
• SELECTION CRITERIA: We included all RCTs of any calcimimetic agent, cinacalcet HCl (AMG-073, Sensipar), NPS R-467 or NPS R-568 administered to patients with CKD for the treatment of SHPT [20].

Gene context of AMG 073

• Direct in vitro evidence of the suppressive effect of cinacalcet HCl on parathyroid hormone secretion in human parathyroid cells with pathologically reduced calcium-sensing receptor levels [21].
• Our investigation examined the genetic polymorphisms of the calcium-sensing receptor (CaSR) gene as one possible cause of the different responses to cinacalcet [22].
• In recent clinical trials in patients with end stage kidney disease, the calcimimetic cinacalcet suppressed parathyroid hormone to a greater degree than conventional therapy with vitamin D analogues without causing hypercalcemia or hyperphosphatemia [23].
• OBJECTIVE: In vitro work has demonstrated that cinacalcet is a strong inhibitor of cytochrome P450 isoenzyme (CYP) 2D6 [24].
• METHODS: Seventeen subjects who were genotyped as CYP2D6 extensive metabolizers were enrolled in this randomized, open-label, crossover study to receive a single oral dose of desipramine (50 mg) on two separate occasions, once alone and once after multiple doses of cinacalcet (90 mg for 7 days) [24].

Analytical, diagnostic and therapeutic context of AMG 073

• Fifty-two hemodialysis patients with secondary hyperparathyroidism were given single orally administered doses of the calcimimetic agent AMG 073 ranging from 5 to 100 mg, or placebo [25].
• This phase 3, multicenter, randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of cinacalcet in hemodialysis (HD) and peritoneal dialysis (PD) patients with PTH > or =300 pg/ml despite traditional therapy [2].
• Serum phosphorus levels and values for the calcium-phosphorus ion product both decreased after treatment with AMG 073 [25].
• Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study [2].
• Cinacalcet HCl was generally well tolerated in clinical trials [17].

References