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1.
Upacicalcet: First Approval.
Hoy, SM
Drugs. 2021;(13):1593-1596
Abstract
Upacicalcet (UPASITA®) is an intravenous calcimimetic agent being developed by Sanwa Kagaku Kenkyusho, under license from EA Pharma, for the treatment of secondary hyperparathyroidism (SHPT), a common and early complication of chronic kidney disease, in patients undergoing haemodialysis. By acting directly on parathyroid cell membrane calcium-sensing receptors, upacicalcet suppresses excessive parathyroid hormone (PTH) secretion, thereby lowering blood PTH levels. Upacicalcet received its first approval on 23 June 2021 for the treatment of SHPT in adults undergoing haemodialysis in Japan. It is administered intravenously three times per week into the venous side of the haemodialysis circuit at the time of blood return at the end of the haemodialysis session. The generally recommended starting dose of upacicalcet is 25 µg, with the dose adjusted within a 25-300 µg range based on PTH and serum calcium levels. This article summarizes the milestones in the development of upacicalcet leading to this first approval for the treatment of SHPT in patients undergoing haemodialysis.
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2.
Tertiary hyperparathyroidism: a review.
Palumbo, VD, Palumbo, VD, Damiano, G, Messina, M, Fazzotta, S, Lo Monte, G, Lo Monte, AI
La Clinica terapeutica. 2021;(3):241-246
Abstract
Tertiary hyperparathyroidism (HPT III) occurs when an excess of parathyroid hormone (PTH) is secreted by parathyroid glands, usually after longstanding secondary hyperparathyroidism. Some authorities reserve the term for secondary hyperparathyroidism that persists after successful renal transplantation. Long-standing chronic kidney disease (CKD) is associated with several metabolic disturbances that lead to increased secretion of PTH, including hyperphosphatemia, calcit-riol deficiency, and hypocalcaemia. Hyperphosphatemia has a direct stimulatory effect on the parathyroid gland cell resulting in nodular hyperplasia and increased PTH secretion. Prolonged hypocalcaemia also causes parathyroid chief cell hyperplasia and excess PTH. Af-ter correction of the primary disorder CKD by renal transplant, the hypertrophied parathyroid tissue fails to resolute, enlarge over and continues to oversecrete PTH, despite serum calcium levels that are within the reference range or even elevated. They also may become resistant to calcimimetic treatment. The main indication for treatment is persistent hypercalcemia and/or an increased PTH, and the primary treatment is surgery. Three procedures are commonly performed: total parathyroidectomy with or without autotransplantation, subtotal parathyroidectomy, and limited parathyroidectomy. It is important to remove superior parts of thymus as well. The most appropriate surgical procedure, whether it be total, subtotal, or anything less than subtotal including "limited" or "focused" parathyroidectomies, continues to be unclear and controversial. Surgical complications are rare, and para-thyroidectomy appears to be a safe and feasible treatment option for HPT III.
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3.
Etelcalcetide versus placebo for secondary hyperparathyroidism in patients receiving hemodialysis: A meta-analysis of randomized controlled trials.
Zhu, Y, Ou, J, Liu, X, Xie, Z
Clinical nephrology. 2020;(4):173-180
Abstract
AIMS: The aim of the study was to evaluate the efficacy and safety of etelcalcetide for the treatment of secondary hyperparathyroidism (SHPT) in patients receiving hemodialysis, and a meta-analysis was performed using randomized controlled trials (RCTs). MATERIALS AND METHODS We searched studies published on PubMed, Cochrane Central Register of Controlled Trials, and Embase to collect RCTs comparing etelcalcetide with placebo for the treatment of SHPT. Unpublished studies and information were also searched in ClinicalTrials. RESULTS Five RCTs involving 1,268 participants were eligible for inclusion in this meta-analysis. Compared with placebo, etelcalcetide contributed to more participants who achieved ≥ 30% reduction in parathyroid hormone (PTH) (relative risk (RR) 8.64; 95% CI, 6.66 to 11.19; p < 0.00001) and a PTH level of ≤ 300 pg/mL (RR 11.80; 95% CI, 8.15 to 17.08; p < 0.00001) as well as an increase in the incidence of hypocalcemia (RR 18.76; 95% CI, 4.55 to 77.26, p < 0.0001), nausea (RR 1.79; 95% CI, 1.19 to 2.70; p = 0.006), or vomiting (RR 1.82; 95% CI, 1.17 to 2.85; p = 0.008). Etelcalcetide reduced serum phosphate (mean difference (MD) -7.28; 95% CI, -8.82 to -5.74; p < 0.00001), calcium phosphorus product (MD -14.48; 95% CI, -15.07 to -13.88; p < 0.00001), and bone-specific alkaline phosphatase (MD -24.80; 95% CI, -28.91 to -20.68) levels compared with the placebo. CONCLUSION Etelcalcetide can effectively control serum PTH and disorder of mineral metabolism but with more side effects than placebo. Further studies comparing etelcalcetide with other medication treatments for SHPT will be needed to evaluate if etelcalcetide might be a valuable choice with less pill burden for patients with SHPT receiving hemodialysis.
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4.
An integrated analysis of safety and tolerability of etelcalcetide in patients receiving hemodialysis with secondary hyperparathyroidism.
Block, GA, Chertow, GM, Sullivan, JT, Deng, H, Mather, O, Tomlin, H, Serenko, M
PloS one. 2019;(3):e0213774
Abstract
BACKGROUND Calcimimetics have been shown to be effective and safe therapies for the treatment of secondary hyperparathyroidism (sHPT), a serious complication of disordered mineral metabolism associated with dialysis-dependent chronic kidney disease. Etelcalcetide, a recently approved intravenous calcimimetic, reduces serum parathyroid hormone (PTH), calcium, phosphorus, and fibroblast growth factor-23 concentrations. Here we report the first integrated safety profile of etelcalcetide using pooled data from five pivotal clinical trials. METHODS This analysis included data from patients receiving hemodialysis with moderate to severe sHPT enrolled in two randomized, placebo-controlled trials; a randomized active-controlled (with cinacalcet) trial; and two single-arm, open-label extension trials. Patients initially received etelcalcetide intravenously 5 mg three times weekly (TIW) after hemodialysis; with potential dose increases of 2.5 or 5 mg at 4-week intervals to a maximum dose of 15 mg TIW, depending on serum PTH and calcium levels. The nature, frequency, and severity of treatment-emergent adverse events (AEs) and changes in laboratory parameters were assessed. RESULTS Overall, we evaluated 1023 patients from the placebo-controlled trials, 683 from the active-controlled trial, and 1299 from open-label extensions. The frequency and nature of common treatment-emergent AEs reported for the etelcalcetide arm were consistent among the placebo-controlled and active-controlled trials. The most common AEs were those related to mineral metabolism (decreased blood calcium, hypophosphatemia, muscle spasms) or gastrointestinal abnormalities (diarrhea, nausea, vomiting). Hypocalcemia leading to discontinuation of either calcimimetic was experienced in ≤ 1% of patients. CONCLUSIONS This integrated safety assessment of etelcalcetide across placebo- and active-controlled trials showed an overall favorable risk/benefit profile, with safety similar to that of cinacalcet. Consistent with its mechanism of action, the most important risks associated with etelcalcetide were serum calcium reductions and hypocalcemia-related AEs; no new safety findings were identified in the pooled long-term extension trials.
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5.
Subtotal parathyroidectomy versus total parathyroidectomy with autotransplantation for secondary hyperparathyroidism: an updated systematic review and meta-analysis.
Yuan, Q, Liao, Y, Zhou, R, Liu, J, Tang, J, Wu, G
Langenbeck's archives of surgery. 2019;(6):669-679
Abstract
PURPOSE The optimal surgical approach of parathyroidectomy for patients with secondary hyperparathyroidism (SHPT) has been controversial. The updated meta-analysis aimed to compare the effectiveness of subtotal parathyroidectomy (SPTX) versus total parathyroidectomy with autotransplantation (TPTX + AT). METHODS A thorough systematic search was performed on the databases of PubMed, EMBASE, and Cochrane library to identify eligible studies. Data were extracted and pooled into a meta-analysis. The primary outcomes were the symptomatic improvement, radiological changes, hypocalcemia rate, the requirement for vitamin D analogues, time to recurrence, recurrence, persistence, and reoperation rates of SPTX versus TPTX + AT. RESULTS A total of 18 studies with 3656 patients (1864 patients in SPTX and 1792 patients in TPTX + AT group) were included, and 15 studies were included in quantitative synthesis. No significant difference was observed in symptomatic improvement (93.3%, 89.0%; P = 0.99), radiological changes (85.4%, 85.3%; P = 0.91), hypocalcemia rate (16.6%, 18.1%; P = 0.29), persistence rate (6.1%, 2.0%; P = 0.16), time to recurrence (mean difference 1.46; P = 0.87), recurrence rate (9.2%, 7.1%; P = 0.76), and reoperation rate (5.3%, 5.8%; P = 0.66) between SPTX and TPTX + AT groups. Longer operative time (150 vs. 120 min), prolonged in-hospital stay (5.0 vs. 4.1 days), lower 1-month serum calcium level, and higher requirement for vitamin D analogues at 12 months were significantly observed in patients who underwent TPTX + AT compared to SPTX. CONCLUSIONS The two surgical approaches were both effective at controlling SHPT in clinical and laboratory terms. However, most of the data shown were not statistically significant. It was acceptable that surgeons chose either SPTX or TPTX + AT for SHPT.
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6.
Cinacalcet plus vitamin D versus vitamin D alone for the treatment of secondary hyperparathyroidism in patients undergoing dialysis: a meta-analysis of randomized controlled trials.
Xu, J, Yang, Y, Ma, L, Fu, P, Peng, H
International urology and nephrology. 2019;(11):2027-2036
Abstract
BACKGROUND Secondary hyperparathyroidism (SHPT) is a common and serious complication of chronic kidney disease, particularly in end-stage renal disease. Currently, both cinacalcet and vitamin D are used to treat SHPT via two different mechanisms, but it is still unclear whether the combination use of these two drugs can be a safe and effective alternative to vitamin D alone. Therefore, the aim of this meta-analysis was to assess the efficacy and safety of cinacalcet plus vitamin D in the treatment of SHPT. METHODS Four electronic databases, including PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, were searched for eligible publications. All randomized-controlled trials comparing cinacalcet plus vitamin D with vitamin D alone in SHPT patients undergoing dialysis were included. Mean difference (MD) with 95% confidence intervals (CIs) and risk ratios (RRs) with 95% CIs were calculated using a random-effects model or fixed-effects model. Sensitivity analysis was conducted by removing any one study successively to estimate the stability of the pooled results, and subgroup analysis was carried out to explore potential sources of heterogeneity, and funnel plots were used to test publication bias. RESULTS A total of 8 randomized-controlled trials involving 1480 patients were included in the study. Compared with vitamin D treatment, the combination use of cinacalcet and vitamin D significantly lowered serum calcium (MD - 0.82, 95% CI - 1.02 to - 0.61, P < 0.001), phosphorus (MD - 0.57, 95% CI - 0.97 to - 0.18, P = 0.005), and calcium × phosphorus product (MD - 9.41, 95% CI - 10.00 to - 8.82, P < 0.001). However, there was no difference in serum parathyroid hormone (PTH, MD 43.99, 95% CI - 49.22 to 137.20, P = 0.35), ≥ 30% reduction in PTH (RR 1.02, 95% CI 0.69-1.52, P = 0.91), and PTH achieve 150-300 pg/ml (RR 0.88, 95% CI 0.68-1.15, P = 0.35). Moreover, the combination therapy did not increase the risk of all adverse events, all-cause mortality, diarrhea, muscle spasms, and headache (all P > 0.05), but had a higher risk of hypocalcemia (RR 17.98, 95% CI 5.68-56.99, P < 0.001), and nausea or vomiting (RR 3.47, 95% CI 2.25-5.35, P < 0.001). CONCLUSIONS In comparison with vitamin D alone, the combination use of cinacalcet and vitamin D significantly lowered serum calcium, phosphorus, and the calcium × phosphorus product, and did not increase the risk of all adverse events, all-cause mortality, diarrhea, muscle spasms, and headache, whereas had no effect on serum PTH and increased the risk of hypocalcemia and nausea or vomiting. Future studies are needed to assess the effects of cinacalcet plus vitamin D on PTH level, cardiovascular events, and other clinical outcomes in larger samples with longer durations.
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7.
Effects of Long-Term Cinacalcet Administration on Parathyroid Gland in Hemodialysis Patients with Secondary Hyperparathyroidism.
Okuno, S, Inaba, M, Ishimura, E, Nakatani, S, Chou, H, Shoji, S, Yamakawa, T
Nephron. 2019;(2):106-113
Abstract
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.
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8.
Long-Term Efficacy and Safety of Evocalcet in Japanese Patients with Secondary Hyperparathyroidism Receiving Hemodialysis.
Yokoyama, K, Shimazaki, R, Fukagawa, M, Akizawa, T, ,
Scientific reports. 2019;(1):6410
Abstract
Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD), and as the disease progresses SHPT is associated with systemic consequences, termed CKD-mineral and bone disorder. Currently, cinacalcet is indicated for the treatment of SHPT; however, cinacalcet is associated with upper gastrointestinal adverse events. Evocalcet has been developed to address these issues, but the long-term safety and efficacy of evocalcet need to be evaluated. To more accurately reflect clinical practice, this phase 3, multicenter, open-label study was specifically designed without a cinacalcet washout period, and focused on those patients who switched from cinacalcet to evocalcet. A total of 137 SHPT patients undergoing hemodialysis were enrolled, of whom 113 switched from cinacalcet to evocalcet. The most frequent type of adverse drug reaction was decreased adjusted calcium. The incidence of gastrointestinal-related adverse events did not increase in a dose-dependent manner as the dose of evocalcet was increased. The percentage of patients achieving the target intact parathyroid hormone concentration increased from 40.9% to 72.3% with 52-week treatment. The corrected serum calcium and phosphorus levels remained largely unchanged throughout the study. The long-term safety and efficacy of evocalcet was confirmed using a clinically relevant intra-subject dose-adjustment strategy in SHPT patients undergoing hemodialysis.
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9.
[Pharmacological and clinical profiles of a novel calcimimetic, evocalcet (ORKEDIA®)].
Tokunaga, S, Endo, Y, Kawata, T
Nihon yakurigaku zasshi. Folia pharmacologica Japonica. 2019;(1):35-43
Abstract
Calcimimetics allosterically activate the calcium receptor (CaR) and inhibit the secretion of parathyroid hormone (PTH). Cinacalcet hydrochloride (cinacalcet) has been approved as the first calcimimetic drug for the treatment of secondary hyperparathyroidism (SHPT) in patients with hemodialysis. Cinacalcet improved the achievement of target serum PTH and Ca levels and helped drastically reduce the number of parathyroidectomies. However, cinacalcet has side effects involving the gastrointestinal tract, such as nausea and vomiting, which makes it difficult to increase the dose and may result in reduced compliance. Evocalcet has been developed to improve defects of cinacalcet for management of SHPT. Evocalcet acts as an allosteric modulator of CaR, just like cinacalcet. However, its metabolic pathway is different from that of cinacalcet. The metabolism of evocalcet by cytochrome P450 is very low, so evocalcet has higher bioavailability. As a result, its pharmacologically effective dose for the inhibition of PTH secretion is lower than that of cinacalcet. Evocalcet had less of an effect on the gastrointestinal tract than cinacalcet because of the reduced dose required. In a clinical trial with a randomized, double-blind, head-to-head comparison study, it was also confirmed that the incidence of gastrointestinal-related adverse events was lower in the evocalcet group than in the cinacalcet group. Evocalcet may thus be a potent option for the management of SHPT.
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10.
Population Pharmacokinetic and Pharmacodynamic Modeling of Etelcalcetide in Patients with Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis.
Chen, P, Narayanan, A, Wu, B, Gisleskog, PO, Gibbs, JP, Chow, AT, Melhem, M
Clinical pharmacokinetics. 2018;(1):71-85
Abstract
INTRODUCTION Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). METHODS To assess titrated dosing regimens, population pharmacokinetic (PK) and PK/pharmacodynamic (PKPD) modeling of etelcalcetide was performed using NONMEM 7.2. In this analysis, plasma etelcalcetide, serum parathyroid hormone (PTH) and calcium (Ca) concentration-time data were collected from five phase I, II, and III clinical trials following single or multiple intravenous doses of etelcalcetide ranging from 2.5 to 60 mg. A semi-mechanistic model was used to describe the relationship between etelcalcetide, PTH, and Ca. This model included the role of PTH in Ca regulation, the feedback of Ca onto PTH production via the CaSR, and the activity of etelcalcetide plasma levels in increasing the sensitivity of the CaSR to Ca via the cooperative binding model. The impact of relevant covariates was evaluated by stepwise forward/backward selection. Model evaluation was based on standard goodness-of-fit plots and prediction-corrected visual predictive checks (pcVPCs). Simulation was conducted to evaluate titrated dosing regimens. RESULTS AND DISCUSSION The time courses of etelcalcetide, PTH, and Ca were well-described by the model. The clearance and central volume of distribution (Vc) of etelcalcetide were 0.472 L/h and 49.9 L, respectively, while estimates of the turnover half-lives of PTH and Ca were 0.36 and 23 h, respectively. The extent of interindividual variability in model parameters was low to moderate (6-67%), and no covariates were identified as significant predictors of PK and PD variability. pcVPCs confirmed the predictive ability of the model. CONCLUSIONS The current analysis confirms the putative mechanism of action of etelcalcetide as an allosteric activator of CaSR. Simulations showed that dose titration of etelcalcetide, rather than fixed dose, is needed to effectively decrease the PTH level in patient populations.