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Upacicalcet is a new renally excreted and injectable calcimimetic agent. We evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of single and multiple intravenous administration of upacicalcet in patients with secondary hyperparathyroidism undergoing hemodialysis.This study was a multicenter, randomized, placebo-controlled, double-blinded, dose-escalation study consisting of a single-dose study and a multiple-dose study. The single-dose study consisted of seven dose steps from 0.025 to 0.8 mg. For each step, six patients were randomly assigned 2:1 to receive upacicalcet or a placebo. The multiple-dose study occurred over 3 weeks in three-dose steps from 0.05 to 0.2 mg. For each step, 12 patients were randomly assigned 3:1 to receive upacicalcet or a placebo.The plasma concentration of upacicalcet increased in a dose-dependent manner and was maintained for the next dialysis. Upacicalcet was approximately 80% removed by a single dialysis and did not increase in the plasma concentration with repeated administration. Serum intact parathyroid hormone and corrected calcium (CaUpacicalcet for patients with secondary hyperparathyroidism undergoing hemodialysis could be a calcimimetic agent that acts in a dose-dependent manner and persistently until the next dialysis session. No safety or tolerability issues specific to upacicalcet were found.

Patients with end-stage kidney disease (ESKD) frequently develop left ventricular hypertrophy (LVH), which is associated with an exceptionally high risk of cardiovascular events and mortality. This review focuses on interventional studies that modify levels of fibroblast growth factor 23 (FGF23) and examine effects on myocardial hypertrophy, cardiovascular events and mortality.Quantitative evaluations of trials of calcimimetics found no effects on cardiovascular events and cardiovascular and all-cause mortality when compared with placebo. However, a recent randomized, controlled trial of etelcalcetide versus alfacalcidol showed that etelcalcetide effectively inhibited the progression of LVH in comparison to vitamin D in patients on haemodialysis after 1 year of treatment. Prior to that, oral calcimimetic treatment has already been shown to reduce left ventricular mass in patients on haemodialysis, whereas treatment with active vitamin D or mineralocorticoids was ineffective in patients with ESKD.Data from a recent trial of etelcalcetide on LVH suggest that FGF23 may be a possible therapeutic target for cardiac risk reduction in patients on haemodialysis. If these findings are confirmed by further research, it might be speculated that a treatment shift from active vitamin D towards FGF23-lowering therapy may occur in patients on haemodialysis.

This study described control of parathyroid hormone (PTH), phosphorus, and corrected calcium in adults initiating calcimimetics in small dialysis organizations after the introduction of etelcalcetide.This retrospective study using Visonex Clarity electronic health records between October 1, 2017, and December 31, 2019, identified adults ≥ 18 years of age receiving in-center hemodialysis as either a cinacalcet or etelcalcetide initiator based on their first calcimimetic use in 2018 (index date) with no prior calcimimetic use in the 3 months preindex date. Patients were stratified by PTH at index date and were followed for 15 months. Subcohorts of patients who were persistent on a single calcimimetic for 15 months and of patients who had their calcimimetic changed from cinacalcet to etelcalcetide were also analyzed.A total of 677 patients initiated cinacalcet and 711 initiated etelcalcetide. Mean PTH (pg/ml), phosphorus, and corrected calcium (mg/dl) at baseline were 864, 5.9, and 9.3 for cinacalcet and 804, 5.9, and 9.4 for etelcalcetide, respectively. During follow-up, the proportion of initiators considered in-target (monthly average PTH 600) increased from 48% to 62% with cinacalcet and from 56% to 86% with etelcalcetide in the baseline PTH 600 to 800 subgroup; increased from 30% to 64% with cinacalcet and 31% to 59% with etelcalcetide among those with baseline PTH 800 to 1000; and increased from 14% to 41% with cinacalcet and 12% to 58% with etelcalcetide among those with baseline PTH ≥1000. A similar pattern was observed for persistent users (n = 646). For patients changed from cinacalcet to etelcalcetide (n = 183), the proportion of patients considered in-target increased from 22% in the month prior to the treatment change to 51% in Month 6 postchange.Patients initiating calcimimetics at lower baseline PTH had better biochemical control than patients starting at higher PTH. Patients changed from cinacalcet to etelcalcetide had improvements in PTH control postchange.

The aim of the study was to investigate the effect of a new calcimimetic, Etelcalcetide, on secondary hyperparathyroidism and its effects in end-stage renal disease (ESRD) patients treated with hemodialysis (HD) compared with hemodialysis (HD) patients not treated with calcimimetics.The cohort study included 203 ESRD patients with secondary hyperparathyroidism (SHPT) who received HD treatment. Total number patients were randomly to two groups. The main group (n=71) included HD patients treated by new calcimimetic Etelcalcetide. The historical group (n=132) was evaluated retrospectively and included patients who had SHPT but did not receive calcimimetic treatment. Serum levels of phosphorus, calcium and parathyroid hormone were compared for 12 months. The primary endpoint of the study was death from any cause, surrogates - cases of fractures, parathyroidectomy, death from cardiovascular (CV) events.The dose of Etelcalcetide changed monthly and averaged 8.58±1.79 mg. The dynamics of parathormone (PTH) indicators showed that the decrease in PTH levels by 30% from basal occurred after 3 months of treatment in 39 (54.9%) and 12 (9.1%) patients of the main group and historical group, respectively (p0.0001). At the end of the study, the target PTH level reached in 52 (73.2%) patients in the main group and only 14 (10.6%) in the comparison group (p0.0001). In addition to the decrease in serum PTH content, in the main group of patients, there was also a decrease in serum calcium and phosphorus levels. During the time to be analyzed, 36 deaths were reported, 61.1% of which were fatal CV events. The proportion of CV events in the mortality structure is more than 70% higher in the historical group than in the group of patients treated with Etelcalcetide, and is 69,2% vs 40,0%, respectively. The frequency of fractures is almost three times higher in the historical than in the main group of patients. The proportion of patients who required parathyroidectomy was significantly more than three times higher in the historical group than in the main group (p0,05).In a prospective study, we demonstrated the high efficacy of Etelcalcetide in the treatment of SHPT in hemodialysis patients. Treatment of SHPT with the inclusion of Etelcalcetide is accompanied by improved clinical outcomes such as the incidence of bone fractures, cardiovascular morbidity and mortality.

Purpose Secondary hyperparathyroidism (SHPT) is common among dialysis patients, and calcimimetics are a mainstay of treatment. This study assessed whether cinacalcet use is associated with gastrointestinal bleeding in a large hemodialysis cohort. Methods A linked database of clinical records and medical claims for patients receiving hemodialysis in a large dialysis organization, 2007-2010, was used. A nested case-control study was performed among patients aged ≥18 years who had received hemodialysis for ≥90 days, had Medicare Parts A, B, and D coverage for ≥1 year, and had clinical evidence of SHPT (parathyroid hormone >300 pg/mL). Cases were those who experienced death or hospitalization caused by gastrointestinal bleeding. Each case was matched to up to four controls. Exposure was measured by any cinacalcet use, current use, past use, cumulative exposure days, and cumulative dosage. Conditional logistic models were used to assess the association. Results Of 48 437 patients included, 2570 experienced gastrointestinal bleeding events (2498 non-fatal, 72 fatal), and 2465 (2397 non-fatal, 68 fatal) were matched to 9500 controls; 17.2% of cases and 15.8% of controls had cinacalcet exposure and 11.1% of both cases and controls had current use. The adjusted odds ratios (95% CI) of gastrointestinal bleeding for any use, current use, and past use of cinacalcet were 1.04 (0.91-1.19), 0.97 (0.83-1.13), and 1.22 (0.99-1.50), respectively, with no use as the reference. Conclusion The results do not suggest an elevated risk of gastrointestinal bleeding resulting in hospitalization or death for hemodialysis patients exposed to cinacalcet.

Advanced chronic kidney disease with mineral and bone disorder have a significant obstacles to control serum bone profile [serum intact parathyroid hormone (iPTH), calcium and phosphorus] which subsequently have major effect on optimal bone strength, final adult height, and cardiovascular health. A retrospective, observational study, including a total of 36 children with end-stage kidney disease (ESKD). Fourteen children who were prescribed cinacalcet had been compared with the remaining 22 children who were managed with standard care. We report the efficacy and safety of cinacalcet for treatment of refractory secondary hyperparathyroidism (SHPT) in children with ESKD. After 6 months of cinacalcet treatment, the mean level of iPTH serum level decreased by 56% from 202 pmol/L [95% confidence interval (CI): 150-253] to 88 pmol/L (95% CI: 41-136), compared to the change observed in the control group (P0.001). None of our patients reported serious adverse effects or developed hypocalcemia. Cinacalcet could be an effective and safe alternative to treat severe SHPT in children with ESKD. Further long-term and large-scale studies are necessary to confirm its safety and efficacy.

ispartof: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM vol:107 issue:8 pages:E3532-E3533 ispartof: location:United States status: published

Background Renal hyperparathyroidism is a disease entity that is complex and poorly understood. Although there are guidelines regarding how to manage this patient group, evidence is scarce. Therefore, this survey-based study aims to map the physicians’ attitude in terms of preference for management of renal hyperparathyroidism and the influence of patient and respondent factors. Methods A survey was sent to Dutch societies of nephrology, endocrinology, and surgeons with interest in endocrine surgery. The survey consisted of eight case vignettes of renal hyperparathyroidism patients who were on hemodialysis and suitable for kidney transplantation, and varied in one of three patient variables import for decision making: age (40 vs. 65 years), parathyroid hormone (40 vs. 90 pmol/L), and serum calcium level (2.25 vs. 2.8 mmol/L). For each case, respondents could choose between maintaining conservative treatment (active vitamin D metabolites), calcimimetics, or subtotal parathyroidectomy as their treatment of choice. Categorical multilevel logistic models were used to investigate the association of patient and respondent variables with treatment preference. The influence of patient variables was determined independently of each other and by means of logistic regression the probabilities of treatment choice were calculated. Results In total, 115 surveys were included in the analysis. In 6 out of 8 cases, less than two-thirds of respondents agreed on the most favoured treatment. Among patient characteristics, the main disincentive for respondents not to choose conservative therapy was an elevated serum calcium level (subtotal parathyroidectomy vs conservative OR 93.1, 95%-CI: 48.39–179.07 and calcimimetics vs conservative OR 31.2 95%-CI: 18.58–52.30). Additionally, the most significant treatment differences were found between medical specialties and the experience of the respondents, expressed as the amount of cases the physician was involved in during the past year. Conclusions Elevated serum calcium levels were widely recognized and the prime reason for respondents to abandon conservative treatment. However, considerable disagreement in treatment preferences remained throughout the cases, demonstrating the current literature available being inconclusive in guiding physicians. Therefore, a high-quality trial comparing subtotal parathyroidectomy to medical treatment is needed to determine optimal treatment.

Background Tertiary hyperparathyroidism associated with end-stage renal disease is characterized by progression from secondary hyperparathyroidism to an autonomous overproduction of parathyroid hormone that leads to adverse health outcomes. Rates of parathyroidectomy (PTX) have decreased with the use of calcimimetics. Optimal timing of PTX in relation to kidney transplant remains controversial. We aimed to identify the most cost-effective strategy for patients with tertiary hyperparathyroidism undergoing kidney transplant. Methods We constructed a patient level state transition microsimulation to compare 3 management schemes: cinacalcet with kidney transplant, cinacalcet with PTX before kidney transplant, or cinacalcet with PTX after kidney transplant. Our base case was a 55-year-old on dialysis with tertiary hyperparathyroidism awaiting kidney transplant. Outcomes, including quality-adjusted life years, surgical complications, and mortality, were extracted from the literature, and costs were estimated using Medicare reimbursement data. Results Our base case analysis demonstrated that cinacalcet with PTX before kidney transplant was dominant, with a lesser cost of $399,287 and greater quality-adjusted life years of 10.3 vs $497,813 for cinacalcet with PTX after kidney transplant (quality-adjusted life years 9.4) and $643,929 for cinacalcet with kidney transplant (quality-adjusted life years 7.4). Conclusion Cinacalcet alone with kidney transplant is the least cost-effective strategy. Patients with end-stage renal disease-related tertiary hyperparathyroidism should be referred for PTX, and it is most cost-effective if performed prior to kidney transplant.

Background and objectives With multiple medications indicated for mineral metabolism, dialysis providers can apply various strategies to achieve target phosphate and parathyroid hormone (PTH) levels. We describe common prescribing patterns and practice variation in mineral metabolism treatment strategies over the last decade. Design, setting, participants, & measurements In a cohort of adults initiating hemodialysis at Dialysis Clinic, Inc. facilities, we assessed prescriptions of vitamin D sterols, phosphate binders, and cinacalcet longitudinally. To identify the influence of secular trends in clinical practice, we stratified the cohort by dialysis initiation year (2006–2008, 2009–2011, and 2012–2015). To measure practice variation, we estimated the median odds ratio for prescribing different mineral metabolism treatment strategies at 12 months post–dialysis initiation across facilities using mixed effects multinomial logistic regression. Sensitivity analyses evaluated strategies used after detection of first elevated PTH. Results Among 23,549 incident patients on hemodialysis, there was a decline in vitamin D sterol–based strategies and a corresponding increase in strategies without PTH-modifying agents (i.e., phosphate binders alone or no mineral metabolism medications) and cinacalcet-containing treatment strategies between 2006 and 2015. The proportion with active vitamin D sterol–based strategies at dialysis initiation decreased across cohorts: 15% (2006–2008) to 5% (2012–2015). The proportion with active vitamin D sterol–based strategies after 18 months of dialysis decreased across cohorts: 52% (2006–2008) to 34% (2012–2015). The odds of using individual strategies compared with reference (active vitamin D sterol with phosphate binder) varied from 1.5- to two-fold across facilities in 2006–2008 and 2009–2011 cohorts, and increased to two- to three-fold in the 2012–2015 cohort. Findings were similar in sensitivity analyses starting from first elevated PTH measurement. Conclusions Over time, mineral metabolism management involved less use of vitamin D sterol–based strategies, greater use of both more conservative and cinacalcet-containing strategies, and increased practice variation, suggesting growing equipoise.

Rationale & Objective Comparative benefits and harms of calcimimetic agents used for the treatment of secondary hyperparathyroidism have not been well characterized. We sought to compare the effectiveness of 3 calcimimetic agents using published data. Study Design Systematic review of randomized controlled trials and network meta-analysis. Setting & Study Population Adults with chronic kidney disease enrolled in a clinical trial of a calcimetic agent. Search Strategy & Sources MEDLINE, EMBASE, CENTRAL (from February 7, 2013, to November 21, 2019), and a published meta-analysis. Data Extraction Two reviewers independently extracted the study data, assessed risk of bias, and rated evidence certainty using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Analytical Approach Frequentist network meta-analysis was conducted. The primary review outcomes were achievement of a target reduction in serum parathyroid hormone (PTH) levels and hypocalcemia. Additional outcomes were nausea, vomiting, serious adverse events, all-cause mortality, cardiovascular mortality, heart failure, and fracture. Results 36 trials (11,247 participants) were included. All except 4 trials involved dialysis patients. Median follow-up was 26 weeks (range, 1 week to 21.2 months). Compared with placebo, calcimimetic agents had higher odds of achieving target PTH levels with high or moderate certainty. Etelcalcetide had the highest odds of achieving a PTH target compared with evocalcet (OR, 4.93; 95% CI, 1.33-18.2) and cinacalcet (OR, 2.78; 95% CI, 1.19-6.67). Etelcalcetide appeared to cause more hypocalcemia than cinacalcet and evocalcet. Cinacalcet and to a lesser extent etelcalcetide appeared to cause more nausea than placebo. Differences in risk for mortality, cardiovascular end points, or fractures across calcimimetic agents could not be discerned with sufficient certainty. Limitations Lack of longer-term data; heterogeneous end point definitions. Conclusions Evidence of the benefits of calcimimetic therapy is limited to short-term assessment of a putative surrogate outcome (serum PTH). Although etelcalcetide was associated with the largest reduction in PTH levels, side-effect profiles differed across the 3 calcimimetic agents, making it not possible to identify 1 preferred agent.

Background Etelcalcetide is a second-generation calcimimetic for the management of secondary hyperparathyroidism (SHPT) in patients on dialysis. We performed a post-marketing surveillance (PMS) to obtain information on the safety and efficacy of etelcalcetide in clinical practice in Japan. Methods This PMS enrolled SHPT patients who started initial treatment with etelcalcetide between April 1, 2017 and February 28, 2018 in Japan. Safety [adverse drug reactions (ADRs)] and efficacy [serum intact parathyroid hormone (iPTH), corrected calcium (cCa), phosphorous (P), and alkaline phosphatase (ALP)] were recorded for up to 52 weeks or until treatment discontinuation. Treatment decisions were at the physician’s discretion. Results Of 1226 patients enrolled across 282 centers, safety and efficacy data were available for 1195 and 1192, respectively, while 933 continued treatment to Week 52. The starting dose was 5 mg in 82.0% of patients. There were 218 ADRs in 169 patients (14.1%). Metabolism and nutrition disorders (8.8%), adverse laboratory test results (1.8%), and gastrointestinal disorders (1.6%) were the most frequent classes of ADRs. Hypocalcemia-related ADRs occurred in 104 patients (8.7%). The percentage of patients with iPTH levels within the target range (60–240 pg/mL) steadily increased from 19.5% at Week 0 to 64.1% at Week 52 or last dose. cCa, P, and ALP levels remained well controlled. Conclusion This was the first real-world, large-scale, long-term observational PMS of etelcalcetide in Japan. We did not observe any new safety concerns. Etelcalcetide was associated with clinically relevant improvements in serum iPTH and maintenance of serum cCa, P, and ALP levels.

WOS: 000530171600001 PubMed: 32367310 Background Secondary hyperparathyroidism (SHPT) may persist after renal transplantation (RTx), inducing hypophosphatemia and hypercalcemia that precludes the use of vitamin D analogs. The calcimimetic cinacalcet improved plasma calcium and parathyroid hormone (PTH) levels in randomized controlled trials in adults after RTx, but pediatric data are scarce. Methods In this retrospective study, we analyzed 20 pediatric patients from the Cooperative European Paediatric Renal TransplAnt Initiative (CERTAIN) Registry who received cinacalcet after RTx. The results are presented as median and interquartile range (25th-75th percentile). Results At 13.7 (11.0-16.5) years of age, 20 pediatric patients received a renal allograft. Cinacalcet was introduced at 0.4 (0.3-2.7) years post-transplant at an estimated glomerular filtration rate (eGFR) of 50 (34-66) mL/min/1.73 m(2), plasma calcium of 2.58 (2.39-2.71) mmol/L, age-standardized (z score) phosphate of - 1.7 (- 2.7-- 0.4), and PTH of 136 (95-236) ng/L. The starting dose of cinacalcet was 0.5 (0.3-0.8) mg/kg per day, with a maximum dose of 1.1 (0.5-1.3) mg/kg per day. With a follow-up of 3.0 (1.5-3.6) years on cinacalcet therapy, eGFR remained stable; PTH levels decreased to 66 (56-124) ng/L at the last follow-up (p = 0.015). One patient displayed hypocalcemia (1.8 mmol/L). Cinacalcet was withdrawn in three patients (hypocalcemia, parathyroidectomy, incompliance). Nephrocalcinosis of the graft was not reported. Conclusions This pilot study suggests that cinacalcet as off-label therapy for SHPT after pediatric RTx is efficacious in controlling post-transplant SHPT with acceptable tolerability. Continuing cinacalcet even with normal PTH can lead to dangerous life-threatening hypocalcemia. Therefore, at each subsequent visit, the need to continue cinacalcet must be assessed. Dietmar Hopp Stiftung; European Society for Paediatric Nephrology (ESPN); German Society for Paediatric Nephrology (GPN); AstellasAstellas Pharmaceuticals; NovartisNovartis The authors received financial support from the CERTAIN Registry by a grant from the Dietmar Hopp Stiftung, the European Society for Paediatric Nephrology (ESPN), and the German Society for Paediatric Nephrology (GPN), and by grants from the pharmaceutical companies Astellas and Novartis.

Background Secondary hyperparathyroidism (sHPT), a complication of chronic kidney disease (CKD) characterized by persistently elevated parathyroid hormone (PTH), alterations in calcium-phosphorus homeostasis, and vitamin D metabolism, affects 50% of children receiving dialysis. A significant proportion of these children develop CKD-mineral and bone disorder (CKD-MBD), associated with an increased risk of fractures and vascular calcification. The standard of care for sHPT in children includes vitamin D sterols, calcium supplementation, and phosphate binders. Several agents are approved for sHPT treatment in adults undergoing dialysis, including vitamin D analogs and calcimimetics, with limited information on their safety and efficacy in children. The calcimimetic cinacalcet is approved for use in adults with sHPT on dialysis, but is not approved for pediatric use outside Europe. Methods This review provides dosing, safety, and efficacy information from Amgen-sponsored cinacalcet pediatric trials and data from non-Amgen sponsored clinical studies. Results The Amgen cinacalcet pediatric clinical development program consisted of two Phase 3 randomized studies, one Phase 3 single arm extension study, one open-label Phase 2 study, and two open-label Phase 1 studies. Effects of cinacalcet on PTH varied across studies. Overall, 7.4 to 57.1% of subjects who received cinacalcet in an Amgen clinical trial attained PTH levels within recommended target ranges and 22.2 to 70.6% observed a ≥ 30% reduction in PTH. In addition, significant reductions in PTH were demonstrated in all non-Amgen-supported studies. Conclusions To help inform the pediatric nephrology community, this manuscript contains the most comprehensive review of cinacalcet usage in pediatric CKD patients to date.

A 77-year-old man with a history of hypertension, prostate hyperplasia, and urolithiasis was admitted for acute kidney injury caused by hypercalcemia. Neck ultrasonography showed a large cyst adjacent to the right lower thyroid lobe. Although a 99mtechnetium sestamibi scan was negative, an extremely high intracystic intact parathyroid hormone level suggested that the cyst had a parathyroid origin and that a functional parathyroid cyst was present. Immunohistochemical staining for the calcium-sensing receptor (CaSR) after right lower parathyroidectomy revealed CaSR-positive cells lining the cyst, indicating that the functional parathyroid cyst had originated from the hemorrhagic degeneration of a parathyroid adenoma.

Background and Aims: There are only few data on the influence of cinacalcet on the outcome of parathyroidectomy in patients with renal hyperparathyroidism. Indication and timing of surgery have changed since its introduction, especially with regard to kidney transplantation. Therefore, we retrospectively analyzed patients undergoing parathyroidectomy for renal hyperparathyroidism in our institution. Material and methods: Between 2008 and 2015, 196 consecutive operations in 191 patients were analyzed. About 80 operations (41%) were performed in patients receiving cinacalcet compared with 116 operations (59%) in patients without cinacalcet. Clinical data, preoperative medication, pre- and postoperative laboratory values, type and details of surgery including complications, as well as cardiovascular complications and kidney transplantation with graft function were recorded. Results: Demographical data were similar in patients with or without cinacalcet treatment. A total of 54% of patients received a kidney graft before or after parathyroidectomy. Pre- and postoperative parathormone levels were similar in both groups (preoperatively 755 vs 742 ng/L, postoperatively 50 vs 46 ng/L, p > 0.10), whereas patients with cinacalcet showed significantly lower calcium levels preoperatively (2.28 vs 2.41 mmol/L, p = 0.0002). There was no difference in recurrence or persistence of hyperparathyroidism, duration of surgery, hospital stay, or complication rate. Creatinine levels in patients with tertiary hyperparathyroidism were similar after 1-year follow-up. Conclusion: Cinacalcet did not influence outcome of patients with parathyroidectomy for renal hyperparathyroidism and can be safely offered to patients not responding to medical treatment.

Background: Calcimimetics are used to treat mineral and bone disorder by reducing parathyroid hormone (PTH), calcium (Ca), and phosphorus (Phos). The study objectives were to assess the control of PTH, Ca, and Phos over time in patients receiving cinacalcet or etelcalcetide as well as dosing and time to discontinuation for etelcalcetide. Methods: This was a retrospective cohort study using electronic medical records from small and independent dialysis centers. Adults ≥18 years of age were identified as cinacalcet or etelcalcetide users based on the first calcimimetic received in 2018 (index date). Patients were followed from the index date until parathyroidectomy, kidney transplant, death, or end of data (December 31, 2018). Analyses of mean PTH, Ca, and Phos, as well as target achievement of PTH, Ca, and Phos were conducted over a 9-month period. Discontinuation with etelcalcetide was measured with the Kaplan-Meier estimator. Results: There were 1,346 cinacalcet patients (mean age 60.5 years, 43.5% female, and 47.1% Black) and 1,255 etelcalcetide patients (mean age 63.4 years, 46.6% female, and 38.5% Black). At baseline, the proportions in target were similar for etelcalcetide versus cinacalcet: 36 versus 38% for PTH, 79 versus 80% for Ca, and 43 versus 44% for Phos. Overall, 40–47% of cinacalcet users and 48–62% of etelcalcetide users were observed to be in target for PTH over 9 months. The proportion in target for Phos ranged from 41 to 46% for cinacalcet and 46–51% for etelcalcetide. The proportion in target for Ca ranged from 74 to 78% for cinacalcet and 60–73% for etelcalcetide. Etelcalcetide 12-month discontinuation was 37.4%. Conclusion: Both calcimimetics were effective in keeping PTH, Ca, and Phos levels within target. Patients receiving etelcalcetide tended to have lower laboratory values for PTH, Ca, and Phos over time, while patients receiving cinacalcet tended to be more likely to be in target for Ca over time.

Upacicalcet sodium hydrate is a novel small-molecule calcimimetic and has potential as a therapeutic agent for secondary hyperparathyroidism. We assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of a single intravenous dose of upacicalcet in Japanese healthy adults.This was a single-center, double-blinded, randomized, placebo-controlled, dose-escalation study. For each cohort, eight subjects were randomly assigned at a ratio of 3:1 to receive a single injection of placebo or upacicalcet 0.01, 0.1, 1.0, or 2.5 mg.The plasma concentration of upacicalcet increased in a dose-dependent manner. Upacicalcet rapidly disappeared from plasma after administration. The half-life of upacicalcet was approximately 1-2 h. The major excretion route of upacicalcet was via urine. Serum intact parathyroid hormone decreased in accordance with the upacicalcet dose, from the lowest dose of 0.01 mg. Gastrointestinal disorders occurred in one patient in the 1.0 mg group and in five patients in the 2.5 mg group. All adverse events were nonserious, and no symptomatic hypocalcemia occurred.This study showed that upacicalcet acted as a calcimimetic and was excreted in the urine unchanged with little metabolism. Moreover, upacicalcet is a small molecule and has a small volume of distribution. In addition, less than 50% of upacicalcet binds to human plasma proteins. These findings suggest that upacicalcet administered to patients undergoing hemodialysis might be expected to have a long excretion period and sustained pharmacological effect.

Chronic kidney disease (CKD) is a complex and multifactorial disease, and one of the most prevalent worldwide. Chronic kidney disease–mineral bone disorders (CKD–MBD) with biochemical and hormonal alterations are part of the complications associated with the progression of CKD. Pathophysiology of CKD–MBD focused on abnormalities in serum levels of several biomarkers (such as FGF-23, klotho, phosphate, calcium, vitamin D, and PTH) which are discussed in this review. We therefore examine the prognostic association between CKD–MBD and the increased risk for cardiovascular events, mortality, and CKD progression to end-stage kidney disease (ESKD). Lastly, we present specific treatments acting on CKD to prevent and treat the complications associated with secondary hyperparathyroidism (SHPT): control of hyperphosphatemia (with dietary restriction, intestinal phosphate binders, and adequate dialysis), the use of calcimimetic agents, vitamin D, and analogues, and the use of bisphosphonates or denosumab in patients with osteoporosis.

BACKGROUND: Phosphorus levels in the range seen clinically among patients undergoing dialysis have been reported to attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro. Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels.METHODS: To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia.RESULTS: Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds.CONCLUSIONS: These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.

BACKGROUND Management of chronic kidney disease mineral bone disorder (CKD-MBD) in pediatric patients with end-stage renal disease (ESRD) is challenging. While the use of calcimimetics is well-studied in adults on dialysis, few studies have been performed in pediatrics. Little is known about the use of cinacalcet in young children with ESRD. The aim of this study was to report the efficacy and safety of cinacalcet for treatment of secondary hyperparathyroidism in chronic dialysis patients younger than 5 years. MATERIALS AND METHODS We included children aged < 5 years on chronic dialysis, either hemodialysis (HD) or peritoneal dialysis (PD), who were prescribed cinacalcet for more than 1 month. Retrospective chart review was performed to gather demographics, dialysis prescription, relevant mineral imbalance laboratory parameters, and medications. Data was collected for 6 consecutive months. RESULT 18 patients (9 male), mean age at initiation of cinacalcet was 2.3 years; 13 PD and 5 HD. Average starting dose of cinacalcet: 6.2 mg daily, 0.55 mg/kg/day. Average time on dialysis was 14.4 months. Parathyroid hormone significantly decreased over the 1st month following initiation of cinacalcet from 929 (IQR 572 - 1,056) to 427 (IQR 256 - 778) pg/mL, p = 0.009. Three patients developed asymptomatic hypocalcemia (Ca < 9.4 mg/dL). Serum phosphorous decreased after initiation, and this was persistent at 6 months. Significant improvement in linear growth was observed while on cinacalcet and growth hormone (GH). CONCLUSION Cinacalcet can be effectively used in young children on dialysis with minimal side effects. Good linear growth was seen in patients on cinacalcet and GH therapy. Long-term large scale data is necessary to confirm. Institution-based management algorithm incorporating cinacalcet would be helpful to maintain uniformity in role of cinacalcet for management of CKD-MBD.

Aim Secondary hyperparathyroidism (SHPT), a complication of haemodialysis, is commonly treated with calcimimetics. The impact of dialysates containing different calcium (Ca) concentrations on clinical efficacy of calcimimetics are unclear. We examined whether dialysate Ca concentrations influence the efficacy and dosing of etelcalcetide with concomitant drugs. Methods We performed post hoc analyses of a 52‐week, open‐label, multicentre study of etelcalcetide in Japanese SHPT patients to determine whether dialysate Ca influences the therapeutic effects of etelcalcetide with concomitant drugs. We evaluated the differences in serum intact parathyroid hormone (iPTH), corrected Ca (cCa) and phosphate levels among three dialysate Ca concentration groups (2.5, 2.75 or 3.0 mEq/L Ca). Tartrate‐resistant acid phosphatase 5b (TRACP‐5b) and bone alkaline phosphatase (BAP) levels were also compared. Since the dialysate Ca concentration may influence dose adjustment, we assessed the etelcalcetide and concomitant drug doses. Results There were no clinically meaningful differences in iPTH, cCa and phosphate levels among the 2.5, 2.75 and 3.0 mEq/L groups (n = 34, 64 and 35, respectively) over 52 weeks. At Week 52, more than 82%, 71% and 67% of patients had iPTH, cCa and phosphate levels within target ranges (60‐240 pg/mL, 8.4‐10.0 mg/dL and 3.5‐6.0 mg/dL, respectively) across the three groups. TRACP‐5b and BAP levels decreased by Week 52 regardless of dialysate Ca. Changes in etelcalcetide and concomitant drug doses were generally similar in each group. Conclusion The efficacy and dosing of etelcalcetide with concomitant drugs were essentially unaffected by the dialysate Ca concentration. Patients showed improvements in bone hypermetabolism during treatment., SUMMARY AT A GLANCE This is a small observational study of the effect of dialysate calcium concentrations on etelcalcetide with concomitant drugs in secondary hyperparathyroidism. No statistically significant differences were found between the different dialysate calcium groups suggesting that calcium concentrations in the dialysate do not modulate the effect of etelcalcetide.

Upacicalcet (UPASITA

In 2012, the Japanese Society for Dialysis Therapy (JSDT) established the order of correction of P, corrected Ca (cCa), and whole PTH (w-PTH) in the treatment of Chronic Kidney Disease-Metabolic Bone Disorder (CKD-MBD) as P-first. However, there is no report that analyzes whether this rule is in line with reality and what the adequate rate of P is. Therefore, we analyzed the test values of our 48 patients during the year of 2019 and examined the validity of the results. The results showed that the adequate range rates were 70.8% for P, 100% for cCa, and 89.6% for w-PTH. This result is better than the JSDT Web-based Analysis of Dialysis Data Archives (WADDA) P adequacy rate of 66.2%. Although the guideline is P-first, it is often the case that we cannot reach the adequate level; therefore, healthcare professionals and patients often blame each other. We believe that this is due to the mismatch between the modern era of processed foods covered with P additives and treatment methods (P intake restriction and P-binders). The development of processed foods with P additives has brought light and darkness to mankind. The light side is freedom from starvation, and the dark side is a new condition caused by P burden: P burden disease including CKD-MBD.

The calcium‐sensing receptor (CaS receptor) plays a pivotal role in extracellular calcium homeostasis, and germline loss‐of‐function and gain‐of‐function mutations cause familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively. CaS receptor signal transduction in the parathyroid glands is probably regulated by G‐protein subunit α(11) (Gα(11)) and adaptor‐related protein complex‐2 σ‐subunit (AP2σ), and recent studies have identified germline mutations of these proteins as a cause of FHH and/or ADH. Calcimimetics and calcilytics are positive and negative allosteric modulators of the CaS receptor that have potential efficacy for symptomatic forms of FHH and ADH. Cellular studies have demonstrated that these compounds correct signalling and/or trafficking defects caused by mutant CaS receptor, Gα(11) or AP2σ proteins. Moreover, mouse model studies indicate that calcilytics can rectify the hypocalcaemia and hypercalciuria associated with ADH, and patient‐based studies reveal calcimimetics to ameliorate symptomatic hypercalcaemia caused by FHH. Thus, calcimimetics and calcilytics represent targeted therapies for inherited disorders of the CaS receptor signalling pathway. LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc

Patients with chronic kidney disease often develop secondary hyperparathyroidism (SHPT), marked by high levels of circulating parathyroid hormone (PTH) and increased risk of morbidity and mortality. Patients with SHPT are treated with a therapeutic combination that commonly includes calcimimetics, which have recently become popular in clinical settings, and other agents such as vitamin D preparations. Calcimimetics are a drug class that reduces PTH levels by targeting the calcium‐sensing receptor. Cinacalcet, a representative calcimimetic, is widely used; however, a high incidence of upper gastrointestinal (GI) tract‐related adverse events (AEs) can result in insufficient dosage and poor long‐term compliance. The newly approved evocalcet has equivalent efficacy to cinacalcet at a lower clinical dose, with improved bioavailability, fewer upper GI tract‐related AEs, and fewer safety concerns. This review gives an overview of calcimimetic agents, with a special focus on evocalcet, and describes the clinical advantages of evocalcet in the treatment of dialysis patients with SHPT.

Secondary hyperparathyroidism is a frequent complication of chronic kidney disease that begins early in the course of renal insufficiency as an adaptive response to maintain mineral homeostasis. This complex disorder affects the bone, leading to an increase in fracture risk and is associated with increased risks of vascular calcification and mortality. PURPOSE OF REVIEW: In this review, we examine the different strategies available to manage secondary hyperparathyroidism. Particularly, we focus on the adequate control of serum phosphorus by restricting intake and the use of phosphate binders, correction of hypocalcemia while minimizing calcium burden, and reduction in PTH levels through the use of vitamin D sterols and calcimimetics. RECENT FINDINGS: It was observed that although numerous agents directed at the correction of these abnormalities have demonstrated effectiveness on biochemical markers, there is still a relative scarcity of studies demonstrating treatment effectiveness as measured by hard clinical outcomes. In addition, most agents have side effects that may limit their use, even in patients in which the treatment has demonstrated efficacy in controlling these parameters. There is still controversy as to what therapeutic regimens to choose for a particular patient and what parameter should be used to follow their effects, including outcomes, side effects, pill burden, and costs, among others. In the present article, we analyze controversial aspects of the different therapeutic agents available. Although many tools and regimens are available, no one by itself is enough for an adequate management of the patient. But rather, combined therapy and individualization of approaches are recommended for better results. We suggest that new studies analyzing the effectiveness of therapeutic approaches to the management of secondary hyperparathyroidism should be directed not only to controlling parathyroid hormone levels but also to the evaluation of long-term outcomes, based on modification of morbidity, mortality, and end organ impact, while reducing side effects and controlling costs, among others.

Objective In dialysis patients, cinacalcet could be an effective alternative to parathyroidectomy for treating hyperparathyroidism. In the present study, we aimed to determine the characteristics of subjects with persistent hyperparathyroidism who require parathyroidectomy despite the use of cinacalcet. Methods Nine kidney transplant patients (7 men, 2 women; mean age 53.2 [SD, 8.9] years) who had tertiary hyperparathyroidism were reviewed in a single center. Pre- and postcinacalcet levels of calcium, phosphorous, intact parathyroid hormone (iPTH), and renal function were analyzed to evaluate the effect of cinacalcet treatment in these patients. The baseline parameters before cinacalcet treatment were compared in patients who did and did not undergo parathyroidectomy. Results Cinacalcet reduced serum calcium levels in all patients (11.48 [SD, 0.73] mg/dL to 10.20 [0.70] mg/dL; P = .008). Serum phosphorous levels significantly increased from 2.28 (SD, 0.77) mg/dL to 3.02 (SD, 0.65) mg/dL (P = .03). The iPTH levels in 7 patients decreased, while the mean level remained unchanged in total subjects. The iPTH levels increased even with cinacalcet treatment in 2 patients. In 3 patients, serum calcium levels abruptly increased after cinacalcet withdrawal. Five patients who showed persistent hypercalcemia due to hyperparathyroidism underwent parathyroidectomy. These 5 patients had significantly different characteristics compared with 4 patients who did not undergo parathyroidectomy: hypercalcemia (11.92 [SD, 0.68] mg/dL vs 10.93 [SD, 0.26] mg/dL; P = .02), hypophosphatemia (1.74 [SD, 0.36] mg/dL vs 2.95 [SD, 0.58] mg/dL; P = .03), and hyperparathyroidism (252.2 [SD, 131.4] pg/dL vs 101.5 [SD, 18.4] pg/dL; P = .02). Conclusion Cinacalcet reduced hypercalcemia due to hyperparathyroidism in the transplant patients. However, patients who had pre-existing higher iPTH, hypercalcemia, and hypophosphatemia needed parathyroidectomy. Therefore, cinacalcet could be considered an alternative to parathyroidectomy in selected patients.

AIMS The aims of this study were to develop a pharmacokinetic (PK) and PK-pharmacodynamic (PK/PD) model of cinacalcet in adults and paediatrics with secondary hyperparathyroidism (SHPT) on dialysis, to test covariates of interest, and to perform simulations to inform dosing in paediatrics with SHPT. METHODS Cinacalcet PK, intact parathyroid hormone (iPTH) and corrected calcium (cCa) time courses following multiple daily oral doses (1-300 mg) were modelled using a nonlinear mixed effects modelling approach using data from eight clinical studies. Model-based trial simulations, using adult or paediatric titration schemas, predicted efficacy (iPTH change from baseline and proportion achieving iPTH decrease ≥30%) and safety (cCa change from baseline and proportion achieving cCa ≤8.4 mg/dL) endpoints at 24 weeks. RESULTS Cinacalcet PK parameters were described by a two-compartment linear model with delayed first-order absorption-elimination (apparent clearance = 287.74 L h-1 ). Simulations suggested that paediatric starting doses (1, 2.5, 5, 10 and 15 mg) would provide PK exposures less than or similar to a 30 mg adult dose. The titrated dose simulations suggested that the mean (prediction interval) proportion of paediatric and adult subjects achieving ≥30% reduction in iPTH from baseline at Week 24 was 49% (36%, 62%), and 70.1% (62.5%, 77%), respectively. Additionally, the mean (confidence interval) proportion of paediatric and adult subjects achieving cCa ≤8.4 mg dL-1 at Week 24 was 8% (2%, 18%) and 23.6% (17.5%, 30.5%), respectively. CONCLUSIONS Model-based simulations showed that the paediatric cinacalcet starting dose (0.2 mg kg-1 ), titrated to effect, would provide the desired PD efficacy (PTH suppression