Administration Of Cinacalcet Research Articles

#108 Mineral and bone disorders during chronic kidney disease

Abstract Background and Aims The objectives of our work were to describe mineral and bone disorders in patients with chronic kidney disease (CKD) not yet at the dialysis stage and to assess the compliance of phosphocalcic balance indicators with international KDIGO recommendations Method It was a retrospective study conducted over a 10-month period (01 November 2018 to 31 August 2019) in the nephrology and haemodialysis department of the Renaissance University Hospital in Ndjamena. We have included all patients followed up in the unit for non-dialysis CKD, aged over 18 years and consenting to participate to this study. Results A total of 387 patients files were collected, 82 of which have been taken on. The average age of the patients was 52.7 (± 15.8) years, with a male predominance (67.1%). The comorbidities were arterial hypertension (71.9%) and diabetes (24.4%). CKD has predominated in stage V (55%), followed by stage III (23%). Clinical signs were mainly diffuse bone pain (37.8%), pruritus (8.5%), muscle pain (7.3%) and insomnia (8.5%). Disorders in phosphocalcic metabolism have been noticed in stage IV (11.9% and 10.7%) and stage V (40.5% and 34.5%) for hypocalcaemia and hyperphosphataemia. Secondary hyperparathyroidism and 25 OH vitamin D deficiency were respectively 28.8% and 40.5% in stage V CKD. Compliance with international KDIGO recommendations was 59.7%, 53.7% and 37% respectively for serum calcium, serum phosphorus and parathyroid hormone. Radiological fractures were observed in 4.9% of patients. The management of these disorders has focused on calcium carbonate (52.4%), native vitamin D (64.6%) and Cinacalcet (6.1%) administration. Hypocalcaemia (p = 0.005) and hyperphosphataemia (p = 0.0001) were higher in stage V patients, with a significant difference. Conclusion The treatment of mineral and bone disorders has way to go for the majority of patients, due to lack of resources and the exorbitant cost of treatment. Prevention of mineral and bone disorders is a fundamental pillar of CKD treatment for our patients.

Clinical administration of cinacalcet in parathyroid diseases

Cinacalcet has emerged as an effective therapeutic option for the management of secondary hyperparathyroidism (SHPT) and chronic kidney disease-mineral and bone disorder (CKD-MBD). Through its modulation of the calcium-sensing receptor (CaSR), cinacalcet demonstrates considerable clinical benefits in maintaining parathyroid hormone and serum calcium levels within target ranges. It offers a valuable addition to the available treatment options for patients with these conditions. Cinacalcet binds to the CaSR on parathyroid cells, increasing its sensitivity to extracellular calcium. This results in decreased parathyroid hormone (PTH; parathormone), release through inhibition of intracellular signaling pathways involved in PTH synthesis and secretion. Cinacalcet also indirectly reduces serum calcium and phosphorus levels by suppressing PTH-mediated bone resorption and enhancing renal phosphate excretion.

The impact of cinacalcet on the serum phosphorus, calcium and PTH levels in dialysis patients; a systematic review and meta-analysis

Introduction: Cinacalcet is a medication prescribed to manage hypercalcemia and hyperparathyroidism in patients with chronic kidney diseases. The present study aims to evaluate the impact of cinacalcet on serum levels of calcium, phosphorus, and parathyroid hormone (PTH) in patients undergoing dialysis using a systematic review and meta-analysis approach. Materials and Methods: This study was conducted based on the PRISMA guidelines. A literature search without time restriction was performed on international databases, including Cochrane, Web of Science, Scopus, and PubMed. Data were analyzed using STATA 14 software at a significance level of P<0.05 for all tests. Results: The present meta-analysis involved twelve studies with a sample size of 1131 patients. A reduction was noted in the serum levels of calcium [SMD: -1.32 (95% CI: -2.64, -0.01)], PTH [SMD: -3.95 (95% CI: -6.53, -1.37)], phosphorus [SMD: -1.61 (95% CI: -3.01, -0.20)] and Ca×P [SMD: -5.33 (95% CI: -10.16, -0.49)] after cinacalcet use in dialysis patients. However, the variations in serum levels of alkaline phosphatase were non-significant [SMD: -0.09 (95% CI: -0.94, 0.77)]. In addition, the effectiveness of cinacalcet use on calcium serum level reduction in dialysis patients was verified at a daily dose of 30-60 mg [SMD: -0.83 (95% CI: -1.25, -0.42)] and consumption duration of 24 months [SMD: -1.26 (95% CI: -1.66, -0.87)]. Conclusion: The administration of cinacalcet significantly decreased the serum calcium, phosphorous, PTH, and Ca×P product in dialysis patients. The lowest and highest effects of cinacalcet were found for calcium and Ca×P products, respectively. The prescription of this drug appears more effective in improving hypercalcemia in dialysis patients. Registration: This investigation has been conducted in accordance with the PRISMA checklist, and its protocol was registered on the PROSPERO platform (ID: CRD42023428774).

Prediction of the development of hypocalcemia in primary hyperparathyroidism patients 1–3 days after radical parathyroidectomy

BACKGROUND: It was impossible to predict the development of hypocalcemia following parathyroidectomy (PTE) in patients with primary hyperparathyroidism (PHPT) until now. Hypocalcemia may be accompanied by myalgia, generalized seizures up to tetany, and arrhythmias. Hypocalcemia following PTE can be prevented by preoperative cholecalciferol supplementation. However, patients with severe hypercalcemia above 3 mmol/L do not receive vitamin D due to the risk of hypercalcemia progression. Despite the existing data showing the safety of cholecalciferol therapy in case of mild elevation of serum calcium, not all patients are prescribed vitamin D supplementation, probably due to the lack of a suitable tool to assess the postoperative hypocalcemia risks.AIM: To design a mathematical model and a software tool for predicting hypocalcemia 1–3 days post-PTE in PHPT patients using the patient’s demographic and clinical data, laboratory test results and preoperative therapy status.MATERIALS AND METHODS: This retrospective study included 478 PHPT patients diagnosed with adenomas and carcinomas of the parathyroid gland (PTG) who underwent radical PTE between 1993–2010 or 2018–2020 at the Endocrinology Research Centre. The following parameters were analyzed: sex; age; laboratory markers prior to calcimimetic and antiresorptive therapy: PTH, total calcium, phosphorus; osteocalcin (OC), alkaline phosphatase (ALP), C-terminal telopeptide of type 1 collagen. Also we analyzed 25-hydroxyvitamin D (25(OH)D); bone mineral density (BMD) measured by X-ray densitometry; medical history of low-energy fractures; preoperative therapy with denosumab, bisphosphonates, cinacalcet, cholecalciferol. Categorical gradient boosting (CatBoost) was built to predict the risk of postoperative hypocalcemia.RESULTS: The prevalence of severe osteoporosis is higher in the postoperative hypocalcemia group compared to the nonhypocalcemia group (27% vs. 15%), wherein the frequency of preoperative administration of cholecalciferol in this group is lower (8% vs. 25%). A CatBoost model was built to predict postoperative hypocalcemia using 13 predictors (sex, age, PTH, serum total calcium, phosphorus, OC, BMD reduction, 25(OH)D, administration of cholecalciferol, bisphosphonates, denosumab, and cinacalcet. The proposed model http://194.87.111.169/hypocalcemia for post-PTE hypocalcemia in PHPT patients achieved the following metrics: positive predictive value 73.3%-86.7%; negative predictive value 74.9%-89.3%.CONCLUSION: The model can be used to choose the appropriate preand postoperative approaches for patients who undergo rPTE.

The effect of cinacalcet on hypercalcemia in kidney transplant patients with hyperparathyroidism: systematic review and meta-analysis

Introduction: Following renal transplantation, patients with end-stage renal disease develop parathyroid dysfunction and electrolyte abnormalities, including calcium and phosphate levels. However, cinacalcet is one of the most used medications for hypercalcemia. Therefore, the present systematic review and meta-analysis aimed to investigate the effect of cinacalcet administration on hypercalcemia in patients with renal transplantation. Materials and Methods: The online databases of Cochrane, Web of Science, Scopus, and PubMed were searched until April 2023 using validated keywords. Moreover, PRISMA was used for qualitatively evaluating the studies since the study protocol was registered on the PROSPERO website. In addition, data analysis was conducted using Stata version 14, and the significance level was set at 0.05. Results: The present meta-analysis included 26 studies (24 cohort studies and two randomized clinical trials) investigating 602 patients with renal transplantation and hyperparathyroidism. According to our findings, cinacalcet reduced the serum calcium (MD: -2.24, 95% CI: -2.82, -1.67), parathormone (SMD: -0.85, 95% CI: -1.15, -0.54), and alkaline phosphatase levels (SMD: -0.45, 95% CI: -0.91, -0.01). Moreover, 30-60 mg of cinacalcet per day effectively treated hypercalcemia (SMD: -2.77, 95% CI: -3.57, -1.98), while other doses were not significantly effective. Furthermore, the effect of cinacalcet was investigated in patients using the medication for less than six months (SMD: -2.55, 95% CI: -4.25, -0.86), 12-18 months (SMD: -2.60, 95% CI: -3.53, -1.67), and more than 24 months (SMD: -1.71, 95% CI: -2.54, -0.88). Finally, the effect of cinacalcet was the highest in the patients who were 60-64 years old compared to other age groups (SMD: -3.59, 95% CI: -5.14, -2.04). Conclusion: Cinacalcet could improve hypercalcemia and hyperparathyroidism in patients with renal transplantation. Moreover, the effect of cinacalcet had a direct and positive relationship with the patient’s age. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (ID: CRD42023428620) and Research Registry (UIN: reviewregistry1667) website.

Pharmacological profile of upacicalcet, a novel positive allosteric modulator of calcium-sensing receptor, in vitro and in vivo

Upacicalcet (formerly SK-1403/AJT240) is a novel non-peptide calcimimetic agent that acts as a calcium-sensing receptor (CaSR) agonist for the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). We compared upacicalcet with other calcimimetics (etelcalcetide or cinacalcet) and examined its in vitro and in vivo characteristics in terms of its human CaSR agonistic activity, its efficacy in normal and CKD rats after a single administration, and its effect on gastric emptying in rats. Upacicalcet activated human CaSR depending on the extracellular calcium (Ca2+) concentration without exhibiting an agonistic action when the extracellular Ca2+ level was below the physiological level. On the other hand, etelcalcetide had an agonistic activity even in the absence of physiological levels of extracellular Ca2+. The intravenous administration of upacicalcet to normal and double-nephrectomized rats dose-dependently (0.03–3mg/kg and 0.3–30mg/kg, respectively) decreased the serum intact parathyroid hormone (iPTH) and serum Ca2+ levels; however, the effect of upacicalcet on the reduction in serum Ca2+ disappeared at extracellular Ca2+ levels below the physiologically range, even when administered at a dose higher (100-fold) than the effective dose. Furthermore, upacicalcet did not affect gastric emptying in normal rats when administered up to a dose of 10mg/kg (300-fold higher than the dose affecting serum iPTH levels), while the administration of cinacalcet significantly slowed gastric emptying by approximately 50%. These findings suggest that upacicalcet has potential as an alternative calcimimetic agent with good pharmacological properties and a lower risk of hypocalcemia and gastrointestinal complications.

Pre-operative Cinacalcet Administration Reduces Immediate Post-operative Hypocalcemia Following Total Parathyroidectomy in Severe Renal Hyperparathyroidism.

In severe renal hyperparathyroidism (RHPT), whether administrating Cinacalcet before total parathyroidectomy can reduce post-operative hypocalcemia remains unclear. We compared post-operative calcium kinetics between those who took Cinacalcet before surgery (Group I) and those who did not (Group II). Patients with severe RHPT (defined by PTH ≥ 100pmol/L) who underwent total parathyroidectomy between 2012 and 2022 were analyzed. Standardized peri-operative protocol of calcium and vitamin D supplementation was followed. Blood tests were performed twice daily in the immediate post-operative period. Severe hypocalcemia was defined as serum albumin-adjusted calcium < 2.00mmol/L. Among 159 patients who underwent parathyroidectomy, 82 patients were eligible for analysis (Group I, n = 27; Group II, n = 55). Demographics and PTH levels before Cinacalcet administration were comparable (Group I: 169 ± 49pmol/L vs Group II: 154 ± 45, p = 0.209). Group I had significantly lower pre-operative PTH (77 ± 60pmol/L vs 154 ± 45, p < 0.001), higher post-operative calcium (p < 0.05), and lower rate of severe hypocalcemia (33.3% vs 60.0%, p = 0.023). Longer duration of Cinacalcet use correlated with higher post-operative calcium levels (p < 0.05). Cinacalcet use for > 1year resulted in fewer severe post-operative hypocalcemia than non-users (p = 0.022, OR 0.242, 95% CI 0.068-0.859). Higher pre-operative ALP independently correlated with severe post-operative hypocalcemia (OR 3.01, 95% CI 1.17-7.77, p = 0.022). In severe RHPT, Cinacalcet led to significant drop in pre-operative PTH, higher post-operative calcium levels, and less frequent severe hypocalcemia. Longer duration of Cinacalcet use correlated with higher post-operative calcium levels, and the use of Cinacalcet for > 1year reduced severe post-operative hypocalcemia.

Potential cinacalcet‐clozapine interaction

Clozapine's use in the management of patients with treatment‐resistant schizophrenia has been limited by the occurrence of significant side effects. Also, because its elimination is primarily mediated by multiple drug‐metabolizing enzymes, the potential for drug–drug interaction is high. The following case described an elderly patient who developed dystonic reactions with concurrent administration of clozapine and cinacalcet, a calcimimetic used to treat patients with tertiary hyperparathyroidism, parathyroid carcinoma, and primary hyperparathyroidism.1

Glucose/Fructose Delivery to the Distal Nephron Activates the Sodium-Chloride Cotransporter via the Calcium-Sensing Receptor.

The calcium-sensing receptor (CaSR) in the distal convoluted tubule (DCT) activates the NaCl cotransporter (NCC). Glucose acts as a positive allosteric modulator of the CaSR. Under physiologic conditions, no glucose is delivered to the DCT, and fructose delivery depends on consumption. We hypothesized that glucose/fructose delivery to the DCT modulates the CaSR in a positive allosteric way, activating the WNK4-SPAK-NCC pathway and thus increasing salt retention. We evaluated the effect of glucose/fructose arrival to the distal nephron on the CaSR-WNK4-SPAK-NCC pathway using HEK-293 cells, C57BL/6 and WNK4-knockout mice, ex vivo perfused kidneys, and healthy humans. HEK-293 cells exposed to glucose/fructose increased SPAK phosphorylation in a WNK4- and CaSR-dependent manner. C57BL/6 mice exposed to fructose or a single dose of dapagliflozin to induce transient glycosuria showed increased activity of the WNK4-SPAK-NCC pathway. The calcilytic NPS2143 ameliorated this effect, which was not observed in WNK4-KO mice. C57BL/6 mice treated with fructose or dapagliflozin showed markedly increased natriuresis after thiazide challenge. Ex vivo rat kidney perfused with glucose above the physiologic threshold levels for proximal reabsorption showed increased NCC and SPAK phosphorylation. NPS2143 prevented this effect. In healthy volunteers, cinacalcet administration, fructose intake, or a single dose of dapagliflozin increased SPAK and NCC phosphorylation in urinary extracellular vesicles. Glycosuria or fructosuria was associated with increased NCC, SPAK, and WNK4 phosphorylation in a CaSR-dependent manner.

Еffectiveness of long-term cinacalcet administration in hemodialysis patients with secondary hyperparathyroidism: A prospective, historically controlled study

Abstract. Our study aimed to determine the long-term effects of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.&#x0D; Materials and methods. The study was conducted in 2 phases. At Phase 1, a retrospective analysis of data from 238 outpatient cards of patients treated with hemodialysis on the Kyiv City Center of Nephrology and Dialysis in 2015-2018 was conducted. According to the inclusion and exclusion criteria, data from 93 patients who made up the historical observation group were selected for further analysis In Phase 2, a prospective cohort study lasting 18 months was conducted. The study included 82 hemodialysis patients treated on the Kyiv City Center of Nephrology and Dialysis in the period from 2019 to 2021. These patients were the main observation group. Patients of the main group were prescribed cinacalcet for the correction of secondary hyperparathyroidism. The primary endpoint of the study was death from any cause, surrogates - deaths from cardiovascular events, fractures, parathyroidectomy.&#x0D; Results. At the end of the follow-up period, the target PTH level was in 48 (64.9%) of the 74 survived patients (main group). In another 22 (29.7%) patients the PTH level was ≥40% lower than the initial level. There were no significant changes in PTH levels in 4 (5.4%) patients. At the end of treatment, the level of PTH in the main group was 398 (385; 521.4) pg/ml (p &lt;0.001). The dose of cinacalcet was 60 (30; 90) mg/day.&#x0D; At patients of the historical group in 18 months observation, the target PTH level was reached in 8 (10.4%) of the 77 survived patients, in 10 (12.9%) patients the PTH level decreased by more than 40% compared to baseline, and in 59 (76, 7%) of patients, there were no significant changes in PTH levels. At the end of treatment, the level of PTH in the historical group was 859.7 (568; 928.9) pg/ml (p&gt; 0.05).&#x0D; 32 (23%) patients reported at least one adverse event (AE) associated with cinacalcet. The stated AEs in most cases were mild and did not require discontinuation of the drug. During the observation period in the historical group, the overall mortality rate was more than 1.7 times higher than in the main group, but this difference was not statistically significant (RR 1.76, 95% CI: 0.796 - 3.905). The cardiovascular mortality in the historical group was more than 2.4 times higher than in the main group, but this difference was not statistically significant (RR 2.47, 95% CI: 0.929 - 6.558). In the main group, 4 cases of fractures were recorded (4.9%). The frequency of fractures in the historical group was 2.4 times higher than in the main group, but this difference was not statistically significant (RR 2.425, 95% CI: 0.803 - 7.32). The difference in the frequency of parathyroidectomies was statistically significant in the historical group and was almost 3.3 times higher than in the main group (RR 3.306, 95% CI: 1.143 – 9.565).&#x0D; Conclusions. The obtained data showed the high efficiency of cinacalcet in the correction of high PTH levels, as well as a beneficial effect on important clinical consequences.

Development of a Hypoparathyroid Male Rodent Model for Testing Delayed-Clearance PTH Molecules.

Parathyroid hormone (PTH) replacement is a promising approach in the management of hypoparathyroidism but long-acting analogues need to be developed. To date, animal models for testing PTH required parathyroidectomy by surgery. We have developed a nonsurgical rodent hypoparathyroid model and tested a delayed-clearance PTH molecule (DC-PTH). The aim of this study was to use cinacalcet to suppress calcium levels in normal rats and to reverse these effects with the administration of PTH or PTH analogues. Male Wistar rats were gavaged with either 30 mg/kg cinacalcet-HCl (cinacalcet) or vehicle only. Animals were then dosed with either single or repeated subcutaneous doses of PTH 1-34 or a DC-PTH at 20 nmol/kg. Control animals received vehicle only. Serum samples were analyzed for ionized calcium (iCa), phosphate, PTH, and DC-PTH. A pharmacokinetic-pharmacodynamic (PK-PD) model was built for cinacalcet, PTH 1-34, and DC-PTH using Phoenix64. Cinacalcet reduced iCa levels between 2 and 24 hours, returning to baseline by 72 hours post dose with nadir at 8 hours (analysis of variance P < .001), associated with a fall in rat PTH. For phosphate there was a variable biphasic response. Single-dose PTH abrogated the cinacalcet-induced fall in iCa for up to 2 hours. DC-PTH prevented the fall in iCa from 4 hours post dose and gave a prolonged response, with iCa levels quicker to return to baseline than controls. DC-PTH has a half-life of 11.5 hours, approximately 44 times longer than human PTH 1-34. The PK-PD models defined the reproducible effect of cinacalcet on iCa and that DC-PTH had prolonged biological activity. The administration of cinacalcet provides a robust and reproducible nonsurgical animal model of hypoparathyroidism. DC-PTH holds promise for the treatment of hypoparathyroidism in the future.

FC 078REAL-WORLD EFFECTIVENESS OF ETELCALCETIDE VS. CINACALCET IN US HEMODIALYSIS PATIENTS: A FACILITY CALCIMIMETIC PREFERENCE APPROACH

Abstract Background and Aims Calcimimetic therapy, including oral cinacalcet and intravenous (IV) etelcalcetide, is often used to control parathyroid hormone (PTH) levels in hemodialysis (HD) patients. In a head-to-head clinical trial, etelcalcetide was superior to cinacalcet on PTH reduction. Given that oral administration of cinacalcet is susceptible to challenges of self-management and adherence, etelcalcetide may be even more effective in the real-world setting. To limit confounding by indication, we used a facility calcimimetic preference approach to investigate the comparative effectiveness of etelcalcetide vs. cinacalcet by estimating effects on PTH and other mineral and bone disorder (MBD) markers in a cohort of US HD patients. Method We used data from the US Dialysis Outcomes and Practice Patterns Study (US-DOPPS), a prospective cohort study of in-center HD patients. During a 6-month run-in period from March to August 2019, we evaluated facility calcimimetic preference by calculating the proportion of calcimimetic users in each facility who were prescribed etelcalcetide (vs. cinacalcet). Among patients with any prescription for a calcimimetic during the 6-month run-in period, we evaluated MBD marker outcomes (PTH, albumin-corrected serum calcium [Ca], serum phosphorus [P]), averaged over the subsequent 6 months, from September 2019 to February 2020. We compared HD facilities that treated &amp;gt;75% of calcimimetic users with etelcalcetide (“Etel-first”) vs. those that treated &amp;gt;75% of calcimimetic users with cinacalcet (“Cina-first”). Linear regression was used to model each continuous outcome. Modified Poisson regression was used to estimate the prevalence ratio (PR) of each MBD marker being out of target (PTH &amp;gt;600 pg/mL, Ca &amp;lt;8.4 mg/dL, P &amp;gt;5.5 mg/dL). All models were adjusted for patient-level and facility-level confounders and accounted for facility clustering using GEE. Results We excluded 38 HD facilities with little-to-no calcimimetic use (&amp;lt;10% use or &amp;lt;5 total users) because calcimimetic preference could not be reliably defined, and 44 HD facilities with no clear calcimimetic preference (25-75% etelcalcetide use among calcimimetic users). The analysis included 2156 calcimimetic users: 969 patients from 45 Etel-first facilities and 1187 patients from 67 Cina-first facilities. In Etel-first (vs. Cina-first) HD facilities, the mean difference in PTH levels (primary outcome) was -99 pg/mL (95% CI: -179, -19) and the prevalence of PTH &amp;gt;600 was lower (PR=0.75; 95% CI: 0.60, 0.94) in adjusted models. The adjusted mean levels of serum Ca and serum P (secondary outcomes) were slightly lower in Etel-first (vs. Cina-first) facilities [Table 1]. Conclusion To our knowledge, this is the first large-scale comparison of IV etelcalcetide with oral cinacalcet in the real-world setting. Our unique approach resembles a natural experiment by leveraging practice variation across the US and isolating HD facilities with a clear preference for one calcimimetic. Thus, the prescribed calcimimetic type for included patients was more likely determined by facility preference than biased by patient indication. Our results indicate better PTH control (mean levels ∼100 pg/mL lower) in US HD facilities using etelcalcetide (vs. cinacalcet) as the primary calcimimetic therapy. Further research is needed to investigate the degree to which the greater real-world effectiveness of IV etelcalcetide (vs. oral cinacalcet) may be driven by adherence to the prescribed therapy, and how clinical outcomes may be affected.

Parathyroidectomy or cinacalcet: Do we still not know the best option for graft function in kidney-transplanted patients? A meta-analysis

BackgroundTertiary hyperparathyroidism occurs in 25% to 50% of kidney-transplanted patients. Indication of parathyroidectomy is now discussed, since the calcimimetic agent, cinacalcet, is an alternate option. The effects of either of these treatments on graft function remain controversial, studied only in small cohorts showing either decrease or absence of modification. We performed a meta-analysis to evaluate the evolution of graft function after surgical or medical treatment. MethodsStudies assessing graft function in tertiary hyperparathyroidism after parathyroidectomy or cinacalcet introduction were enrolled into quantitative analysis using Pubmed, Embase, and Cochrane databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis reporting guidelines. Among 68 screened studies, 18 had no missing data and were included for statistical analyses. We performed random effect meta-analysis to determine changes in serum creatinine and estimated glomerular filtration rate. ResultsSeven studies assessing the evolution of graft function 6 and/or 12 months after parathyroidectomy and 13 after administration of cinacalcet were included. Meta-analysis found no significant variations after parathyroidectomy in serum creatinine (6 studies, 314 patients) and estimated glomerular filtration rate (2 studies, 105 patients). No significant variation was found after administration of cinacalcet in serum creatinine (10 studies, 404 patients) and estimated glomerular filtration rate (6 studies, 149 patients). A significant heterogeneity between the studies (P < .01, Cochran’s Q) was found. ConclusionMeta-analysis shows that parathyroidectomy and cinacalcet do not significantly impair graft function in patients with tertiary hyperparathyroidism. However, the significant heterogeneity between selected studies, partially explained by the lack of consensual definition of tertiary hyperparathyroidism, limits the conclusions of all previously published series.

The effect of evocalcet on vagus nerve activity of the gastrointestinal tract in miniature pigs.

Evocalcet is a novel calcimimetic agent with fewer gastrointestinal (GI) adverse effects compared to cinacalcet. Although it is thought that cinacalcet induces GI side effects through the direct stimulation of the calcium receptor (CaR) expressed in the GI tract, the differences in the direct stimulatory effects of these two drugs on the GI tract have not been reported. In this study, we analyzed the difference in the GI effects of these two calcimimetic agents using miniature pigs by detecting vagus nerve stimulation after oral administration of the agents. Although cinacalcet induced vomiting in miniature pigs, evocalcet never induced emetic symptoms. A significant increase in the vagus nerve action potentials was observed after the administration of cinacalcet. Although the increase of that after the administration of evocalcet was mild and not significant in comparison to that in the vehicle group, it was not significantly different from the vagus nerve action potentials after cinacalcet treatment.

Treatment with Cinacalcet in Hemodialysis Patients with Severe Secondary Hyperparathyroidism, Influences Bone Mineral Metabolism and Anemia Parameters

Background: Due to the premium rate of Chronic Kidney Disease, we have increased our knowledge with respect to diagnosis and treatment of Bone Mineral Disease (BMD) in End- Stage Renal Disease (ESRD). Currently, various treatment options are available. The medication used for Secondary Hyper-Parathyroidism gives promising results in the regulation of Ca, P and Parathormone levels, improving the quality of life. The aim of the present study was to investigate the relation of cinacalcet administration to not only parathormone, Ca and P but also to anemia parameters such as hematocrit and hemoglobin. Materials and Methods: retrospective observational study was conducted in a Chronic Hemodialysis Unit. One-hundred ESRD patients were recruited for twenty-four months and were evaluated on a monthly rate. Biochemical parameters were related to medication prescribed and the prognostic value was estimated. Cinacalcet was administered to 43 out of 100 patients in a dose of 30-120 mg. Results: Significant differences were observed in PTH, Ca and P levels with respect to Cinacalcet administration. Ca levels appeared to be higher at 30mg as compared to 60mg cinacalcet. Furthermore, a decreasing age-dependent pattern was observed with respect to cinacalcet dosage. A positive correlation was observed between Dry Weight (DW) and cinacalcet dose. Finally, a positive correlation between Hematocrit and Hemoglobin and cinacalcet was manifested. Conclusions: Cinacalcet, is a potential cardiovascular and bone protective agent, which is approved for use in ESRD patients to assist SHPT. A novel information was obtained from this study, regarding the improvement of the control of anemia.

370 Comparison of 3x Weekly vs Daily Administration of Oral Cinacalcet for the Control of Secondary Hyperparathyroidism (SHPT) in Patients Receiving Hemodialysis (HD)

370 Comparison of 3x Weekly vs Daily Administration of Oral Cinacalcet for the Control of Secondary Hyperparathyroidism (SHPT) in Patients Receiving Hemodialysis (HD)

Cognitive impairment reversed by cinacalcet administration in primary hyperparathyroidism: a case report

Cognitive impairment reversed by cinacalcet administration in primary hyperparathyroidism: a case report

Pharmacokinetics and pharmacodynamics ofcinacalcet in patients with renal failure receiving hemodialysis and hemodiafiltrationtherapy .

Few studies have focused on the effects of dialysis on cinacalcet. In addition, there is no data available on hemodiafiltration (HDF) all over the world. Therefore, we studied the pharmacokinetics (PK) and pharmacodynamics (PD) of cinacalcet in patients undergoing hemodialysis (HD) or HDF to provide more guiding information on its use in these patients, especially in China. In this open-label, single-dose, single-center study of 7 patients with renal failure who underwent dialysis, patients were randomly allocated to two groups consisting of 4 and 3 patients who received low-flux HD and HDF treatments, respectively. All participants underwent dialysis for 4 hours immediately after receiving single oral doses of a 25mg cinacalcet tablet. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and electrochemical luminescence (EI) were used to determine the cinacalcet plasma concentrations and intact parathyroid hormone (iPTH) serum levels, respectively. Peak concentration (Cmax) and area under the curve (AUC) from time 0 to 24 hours (AUC0-24h) of the low-flux HD therapy group were 21.8±18.6 ng/mL and 145.3±91.8 ng×h/mL, respectively, which were similar to those of the HDF group (30.9±7.9 ng/mL and 161.6±26.5 ng×h/mL, respectively). iPTH concentrations of the HD therapy group decreased after cinacalcet administration and increased following its clearance. However, iPTH levels of subjects receiving HDF therapy did not change. Compared with healthy Chinese subjects, patients with renal failure had a higher Cmax and AUC0-24h, slightly prolonged time to Cmax (tmax) after administration of the same dose of cinacalcet. On HD treatment day, variation trends of iPTH in Chinese patients and healthy subjects were similar and significantly different from that on the HDF treatment day. Considering the high protein binding rate of cinacalcet, this may lead to the great free-drug clearance during HDF treatment.

Effects of Long-Term Cinacalcet Administration on Parathyroid Gland in Hemodialysis Patients with Secondary Hyperparathyroidism

Background/Aim: Cinacalcet, an allosteric modulator of the calcium (Ca) sensing receptor, reduces the level of parathyroid hormone (PTH) in serum as well as parathyroid gland volume following administration in hemodialysis patients with secondary hyperparathyroidism, though long-term results are yet to be reported. Methods: Serum parameters (n = 23), together with total parathyroid gland volume (n = 18), were determined in Japanese hemodialysis patients given cinacalcet treatment for 8 years. Results: Following initiation of cinacalcet therapy, levels of serum Ca, phosphate, and intact PTH were significantly decreased. Furthermore, the baseline total volume of the parathyroid gland was 1,272 mm³ (496–2,836 mm³), which was then decreased after 6 months to 796 mm³ (377–1,146 mm³) and then to 332 mm³ (175–570 mm³) after 8 years. There was significant positive correlation between parathyroid gland volume at the start of cinacalcet treatment and reduction in volume during the 8 years cinacalcet treatment. The dose of phosphate binder was significantly decreased in a time-dependent manner after 8 years of cinacalcet treatment, likely because serum phosphate showed a progressive decrease with the treatment. Conclusion: In the present patients, long-term treatment with cinacalcet progressively decreased the total volume of parathyroid glands, as well as levels of intact PTH and phosphate in serum in a time-dependent manner. On the contrary, cinacalcet administration did not cause secondary failure or over-suppress the transition of parathyroid gland activity to hypoparathyroid status. These results suggest that cinacalcet treatment may postpone the need for parathyroidectomy and/or reduce its use even after long-term administration for up to 8 years.

Cinacalcet Treatment Significantly Improves All-Cause and Cardiovascular Survival in Dialysis Patients: Results from a Meta-Analysis

Objective: To assess the long-term effects including all-cause mortality, cardiovascular mortality, and fracture incidence, of cinacalcet on secondary hyperparathyroidism (SHPT) in patients on dialysis. Methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from their inception to October 2018. Randomized controlled trials (RCTs) and cohort design prospective observational studies assessing cinacalcet for the treatment of SHPT in dialysis patients were included. Data extraction was independently completed by 2 authors who determined the methodological quality of the studies and extracted data in duplicate. Study-specific risk estimates were tested by using a fixed effects model. Results: A total of 14 articles with 38,219 participants were included, of which 10 RCTs with 7,471 participants and 4 prospective observational studies with 30,748 participants fulfilled the eligibility criteria. Compared with no cinacalcet, cinacalcet administration reduced all-cause mortality (relative risk [RR] 0.91, 95% CI 0.89–0.94, p < 0.001) and cardiovascular mortality (RR 0.92, 95% CI 0.89–0.95, p < 0.001), but it did not significantly reduce the incidence of fractures (RR 0.93, 95% CI 0.87–1.00, p = 0.05). Conclusions: The results of this meta-analysis indicated that the treatment of SHPT with cinacalcet may in fact reduce all-cause mortality and cardiovascular mortality among patients receiving maintenance dialysis.