Dong, B.J. Cinacalcet: an oral calcimimetic agent for the management of hyperparathyroidism. Clin. Ther. 27, 1725-1751

School of Pharmacy, University of California-San Francisco, 521 Parnassus Avenue C-152, San Francisco, CA 94143-0622, USA.
Clinical Therapeutics (Impact Factor: 2.73). 12/2005; 27(11):1725-51. DOI: 10.1016/j.clinthera.2005.11.015
Source: PubMed


Uncontrolled hyperparathyroidism (HPT), particularly HPT resulting from chronic kidney disease (CKD), is associated with significant morbidity and cardiovascular mortality. Traditional medical therapy (eg, vitamin D sterols, calcium, phosphate binders) has been inadequate for the management of HPT and its vascular and skeletal complications.
: The goal of this article was to review the efficacy and safety profile of cinacalcet, a second-generation calcimimetic, in the management of HPT secondary to CKD, primary HPT, and parathyroid carcinoma.
MEDLINE, Web of Science, and International Pharmaceutical Abstracts were searched from 1995 to July 2005 using the terms cinacalcet, AMG 073, KRN 1493, calcimimetics, hypercalcemia, and hyperparathyroidism.
Compared with placebo, cinacalcet significantly reduced parathyroid hormone levels within 2 to 4 hours after administration (P < 0.05). In Phase III trials involving 1136 patients with secondary HPT, 56% of those who received cinacalcet achieved the National Kidney Foundation Kidney Disease Outcomes Quality Initiative target of a reduction in parathyroid hormone to <300 pg/mL, 65% achieved a calcium-phosphorus product <55 mg2/dL2, and a respective 49% and 46% achieved normalized serum calcium and phosphorus levels (P < 0.001). Cinacalcet's effects were similar regardless of patients' demographic characteristics, duration or mode of dialysis, severity of HPT, or use of concomitant medical therapy. Preliminary evidence suggests that cinacalcet may reverse cortical bone loss. Cinacalcet was well tolerated, with nausea (31%) and vomiting (27%) being the most commonly reported adverse effects. Hypocalcemia was transient in 5% of patients, was usually asymptomatic, and was corrected by dose reduction.
Based on the available evidence, cinacalcet is effective and well tolerated in the treatment of secondary HPT and refractory parathyroid carcinoma. Its use in primary HPT appears promising. Further investigations are needed to determine if cinacalcet can prevent the long-term complications of HPT and reduce mortality.

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    • "On the other hand, allosteric activators of the CaSR, referred to as type II calcimimetics, activate CaSR through binding to the transmembrane (TM) region, especially TM7, of the receptor and induce a conformational change that increases the receptor's sensitivity to Ca 2+ , resulting in suppression of PTH secretion in the parathyroid gland (Silverberg et al. 1997; Fox et al. 1999; Wada et al. 2000; Goodman et al. 2002). One of the type II calcimimetics, cinacalcet (Mimpara â [Amgen, Thousand Oaks, CA], Sensipar â [Amgen]), has been developed for the treatment of parathyroid carcinoma and hyperparathyroidism secondary to CKD (Block et al. 2004; Dong 2005; Quarles 2005). Calcium homeostasis is tightly regulated and disturbance to this mechanism lead to hypercalcemia or hypocalcemia , both of which can have important pathological consequences including cardiovascular events (Renkema et al. 2008; Taylor and Bushinsky 2009). "
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    ABSTRACT: This study investigates the time-dependent effects of cinacalcet on serum calcium, phosphorus, and parathyroid hormone (PTH) levels in 5/6 nephrectomized (NX) rats with experimental chronic renal insufficiency. In this study, 5/6 NX male, Sprague-Dawley rats were treated with vehicle or cinacalcet (10 mg/kg, oral, 1× daily). On Day 0 (before treatment), Day 12 and 13 after treatment (to approximate the clinical practice), and also at 0, 1, 4, 8, 16, and 24 hours after the last dosing, blood was collected for analysis. After 12 or 13 days of cinacalcet treatment, modest changes were observed in serum Ca and phosphorus (Pi), while PTH decreased by >45% to Sham levels (152 ± 15 pg/mL). Detailed mapping found that cinacalcet caused a significant time-dependent decrease in serum Ca following dosing, reaching a lowest point at 8 hours (decrease by 20% to 8.43 ± 0.37 mg/dL), and then returning to normal at 24 hours. Cinacalcet also caused a significant increase in serum Pi levels (by 18%). To investigate the potential mechanism of action, a broad approach was taken by testing cinacalcet in a panel of 77 protein-binding assays. Cinacalcet interacted with several channels, transporters, and neurotransmitter receptors, some of which are involved in brain and heart, and may impact Ca homeostasis. Cinacalcet dose-dependently increased brain natriuretic peptide (BNP) mRNA expression by 48% in cardiomyocytes, but had no significant effects on left ventricular hypertrophy and cardiac function. The results suggest that cinacalcet's hypocalcemic effect may be due to its nonspecific interaction with other receptors in brain and heart.
    Full-text · Article · Aug 2013
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    • "Calcimimetics are synthetic CaR activators specifically developed for the medical treatment of hypercalcaemia. AMG073, also termed Cinacalcet, is currently the drug of choice and widely use for the medical management of uremic secondary hyperparathyroidism (SHPT) (Dong, 2005). Negative allosteric modulators of the CaR are named calcilytics. "
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    ABSTRACT: Calcium is a crucial second messenger in the cardiovascular system. However, calcium may also be an extracellular first messenger through a G-protein-coupled receptor that senses extracellular concentration (Ca(2+)(o)), the calcium-sensing receptor (CaR). The most prominent physiological function of the CaR is to maintain the extracellular Ca(2+) level in a very tight range by regulating the circulating levels of parathyroid hormone (PTH). This control over PTH and Ca(2+) levels is partially lost in patients suffering from primary and secondary hyperparathyroidism. Allosteric modulators of the CaR (calcimimetics) are the first drugs in their class to become available for clinical use and have been shown to successfully treat certain forms of primary and secondary hyperparathyroidism. In addition, several studies suggest beneficial effects of calcimimetics on cardiovascular risk factors associated with hyperparathyroidism. Although a plethora of studies demonstrated the CaR in heart and blood vessels, exact roles of the receptor in the cardiovascular system still remain to be elucidated. However, several studies point toward a possibility that the CaR might be involved in the regulation of vascular tone. This review will summarize the current knowledge on the possible functions of the CaR and calcimimetics on blood pressure regulation.
    Full-text · Article · Mar 2011 · British Journal of Pharmacology
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    ABSTRACT: El hiperparatiroidismo primario es una enfermedad causada por un adenoma/hiperplasia en las glándulas paratiroides, en la que la hipercalcemia debida a una excesiva secreción de parathormona (PTH) es el rasgo principal, y cuyo único tratamiento definitivo es la cirugía. Hay pacientes en los que la cirugía supone un gran riesgo, o que la rechazan, y en los cuales la hipercalcemia no puede ser controlada mediante el tratamiento médico convencional con hidratación, diuréticos y/o bisfosfonatos. Proponemos el uso de dos fármacos indicados en el tratamiento de la hipercalcemia de otras etiologías: el ácido zoledrónico, bisfosfonato de uso parenteral, y el cinacalcet, calcimimético que disminuye la secreción de PTH. Presentamos el caso de una mujer con hipercalcemia por un hiperparatiroidismo primario causado por un adenoma, tratado con ambos fármacos.
    No preview · Article · Mar 2009 · Endocrinología y Nutrición
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