Review

Authors: Francisco Bandeira, Janiere de Moura Nóbrega, Lucian Batista de Oliveira...

Primary hyperparathyroidism (PHPT) is an endocrine disorder resulting from the hyperfunction of one or more parathyroid glands, with hypersecretion of parathyroid hormone (PTH). It can be managed by parathyroidectomy (PTX) or non-surgically. Medical therapy with pharmacological agents is an alternative for those patients with asymptomatic PHPT who meet guidelines for surgery but are unable or unwilling to undergo PTX. In this review, we focus upon these non-surgical aspects of PHPT management. We emphasize the most studied and widely used pharmacological alternatives: bisphosphonates, denosumab, cinacalcet and hormone therapy, in addition to combined therapy. We also address the relevant aspects of perioperative management.

Topics: Humans; Hyperparathyroidism, Primary; Parathyroidectomy; Cinacalcet; Parathyroid Hormone; Parathyroid Glands

PubMed: 36382758
DOI: 10.20945/2359-3997000000558

Authors: J Wang, G-G Chen, L-L Ren...

OBJECTIVE

The aim of the study was to improve the bioavailability of Cinacalcet hydrochloride (CLC) and enhance its efficacy by the nanoemulsion drug delivery system.

MATERIALS AND METHODS

First, cinacalcet hydrochloride-nanoemulsion (CLC-NE) was prepared and optimized through the pseudo ternary phase diagram and central composite design response surface methodology (CCD). The release of CLC-NE in vitro was investigated with four different dissolution media, and the bioavailability of CLC-NE in vivo was studied through beagle dogs. Finally, the pharmacodynamics of CLC-NE was evaluated by the rat model of uremia.

RESULTS

Oleic acid, op-10, and PEG-200 were selected as oil phase, emulsifier, and co-emulsifier, respectively. The optimum ratio of oleic acid, op-10, PEG-200, and water was 9.87%, 38.33%, 12.78%, and 39.02%. CLC-NE has similar dissolution rates in different pH media, and the relative bioavailability of CLC-NE was 166.5%. The uremia model showed that CLC-NE could enhance renal function and reduce the excessive phosphorus (P), serum creatinine (Scr), and urea nitrogen (Urea) of model rats, as well as the inhibited increase of fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH).

CONCLUSIONS

The solubility, bioavailability, and pharmacodynamics of CLC can be significantly improved through the nanoemulsion drug delivery system.

Topics: Animals; Biological Availability; Cinacalcet; Dogs; Drug Delivery Systems; Emulsions; Female; Humans; Male; Nanoparticles; Oleic Acid; Particle Size; Rats; Solubility; Urea; Uremia

PubMed: 35503601
DOI: 10.26355/eurrev_202204_28632

Authors: Feng He, Cheng-Guo Wu, Yang Gao...

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that has a central role in regulating systemic calcium homeostasis. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional G versus G proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both G and G drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective G and G coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands.

Topics: Humans; Allosteric Regulation; Cinacalcet; Cryoelectron Microscopy; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gq-G11; Heterotrimeric GTP-Binding Proteins; Ligands; Lipids; Nanostructures; Polyamines; Protein Conformation; Receptors, Calcium-Sensing; Substrate Specificity; Tryptophan; Calcium

PubMed: 38326620
DOI: 10.1038/s41586-024-07055-2

Randomized Controlled Trial

Authors: Geoffrey A Block, David A Bushinsky, Sunfa Cheng...

IMPORTANCE

Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects.

OBJECTIVE

To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet.

DESIGN, SETTING, AND PARTICIPANTS

A randomized, double-blind, double-dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015.

INTERVENTIONS

Etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily.

MAIN OUTCOMES AND MEASURES

The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self-reported nausea or vomiting.

RESULTS

The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was -10.5% (95% CI, -17.5% to -3.5%, P for noninferiority, <.001; P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to cinacalcet (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%).

CONCLUSIONS AND RELEVANCE

Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT1896232.

Topics: Administration, Oral; Biomarkers; Calcimimetic Agents; Calcium; Cinacalcet; Double-Blind Method; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism, Secondary; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Nausea; Parathyroid Hormone; Peptides; Renal Dialysis; Time Factors; Vomiting

PubMed: 28097356
DOI: 10.1001/jama.2016.19468

Authors: Yang-Jie Liu, Lu-Ning Sun, Zi-Ping Cheng...

BACKGROUND

Our study aims to explore the effect of genetics on the pharmacodynamics (PD) and pharmacokinetics (PK) of cinacalcet in healthy Chinese subjects; to investigate the effect of dietary factors on cinacalcet, and to evaluate the safety of cinacalcet under fasting and non-fasting conditions using a bioequivalence trial.

METHODS

We investigated the relationship of cinacalcet PK with single nucleotide polymorphisms (SNPs) of CYP3A4, CYP1A2 and CYP2D6, and of cinacalcet PD with SNPs of calcium-sensitive receptors (CASR) and vitamin D receptors (VDR) in 65 healthy Chinese subjects recruited to participate in this study. Our study was a phase I, open-label, randomized, two-period, two-sequence crossover, a single-center clinical study designed under both fasting and non-fasting conditions to investigate the effect of dietary factors on cinacalcet. Plasma cinacalcet concentrations were analyzed using a validated HPLC-MS/MS assay. Clinical laboratory tests evaluated safety. Thirteen SNPs of CASR, VDR, and CYP genes were selected for pharmacogenetic analysis.

RESULTS

CYP3A4 rs4646437 was found to be associated with the PK of cinacalcet under fasting conditions (P<0.01). Subjects carrying T alleles of rs4646437 appeared to metabolize cinacalcet poorly. The C and AUC of subjects in the non-fasting group were significantly higher (P<0.0001) than those in the fasting group. The T, CL/F, and Vd/F in the fasting group were significantly higher (P<0.0001) than those in the non-fasting group. In the fasting group, the geometric least square mean ratios (T/R) of the C and AUC were 109.89% and 105.33%, and the corresponding 90% CIs were 98.36-122.79% and 98.04-113.15%, respectively. In the non-fasting group, the T/R of the C and AUC were 100.74% and 99.09%, and the corresponding 90% CIs were 92.65-109.54% and 94.79-103.58%, respectively. All adverse events (AEs) were mild, and no serious adverse events (SAEs) occurred during the bioequivalence trial.

CONCLUSIONS

Following our investigation, we reached the following conclusions: CYP3A4 rs4646437 may affect cinacalcet PK; the reference and test preparations of cinacalcet were bioequivalent under fasting and non-fasting conditions and were safe to use; and dietary factors had a significant effect on the PK of cinacalcet, in that exposure to the drug increased when cinacalcet was taken after eating.

PubMed: 33313130
DOI: 10.21037/atm-20-1329

Authors: Lorenzo Scappaticcio, Arif Nur Muhammad Ansori, Pierpaolo Trimboli...

Topics: Humans; Hypercalcemia; Cinacalcet; Calcium; Neoplasms

PubMed: 37780626
DOI: 10.3389/fendo.2023.1281731

Authors: Cheng Han Ng, Yip Han Chin, Marcus Hon Qin Tan...

PURPOSE

Primary hyperparathyroidism (PHPT) is a common condition affecting people of all ages and is mainly treated with parathyroidectomy. Cinacalcet has been widely used in secondary or tertiary hyperparathyroidism, but the use of cinacalcet in PHPT is less clear.

METHODS

Searches were conducted in Medline and Embase for cinacalcet use in PHPT from induction to 10 April 2020. Articles and conferences abstracts describing the use of cinacalcet for PHPT in prospective or retrospective cohorts and randomized controlled trials restricted to English language only. We initially identified 1301 abstracts. Each article went extraction by two blinded authors on a structured proforma. Continuous outcomes were pooled with weight mean difference (WMD). Quality of included articles was assessed with Newcastle Ottwa Scale and Cochrane Risk of Bias 2.0.

RESULTS

Twenty-eight articles were included. Normalization rate of serum Ca levels was reported at 90% (CI: 0.82 to 0.96). Serum levels of Ca and PTH levels were significantly reduced (Ca, WMD: 1.647, CI: -1.922 to -1.371; PTH, WMD: -31.218, CI: -41.671 to -20.765) and phosphate levels significantly increased (WMD: 0.498, CI: 0.400 to 0.596) after cinacalcet therapy. The higher the baseline Ca levels, the greater Ca reduction with cinacalcet treatment. Age and gender did not modify the effect of cinacalcet on serum Ca levels.

CONCLUSION

The results from the meta-analysis support the use of cinacalcet as an alternative or bridging therapy to treat hypercalcemia in people with PHPT.

PubMed: 32621588
DOI: 10.1530/EC-20-0221

Observational Study

Authors: Aileen X Wang, Sai Liu, Maria E Montez-Rath...

RATIONALE & OBJECTIVE

Posttransplant hyperparathyroidism is common, and treatment practices are poorly characterized. The goal of this study was to examine the incidence, associations, and outcomes of posttransplant parathyroidectomy and calcimimetic use in a cohort of Medicare-insured US kidney transplant recipients.

STUDY DESIGN

Retrospective observational cohort study.

SETTING & PARTICIPANTS

We used the US Renal Data System to extract demographic, clinical, and prescription data from Medicare Parts A, B, and D-insured patients who received their first kidney transplant in 2007-2013. We excluded patients with pretransplant parathyroidectomy.

PREDICTORS

Calendar year of transplantation and pretransplant patient characteristics.

OUTCOME

(1) Incidence of and secular trends in parathyroidectomy and cinacalcet use in the 3 years after transplant; (2) 90-day outcomes after posttransplant parathyroidectomy and cinacalcet initiation.

ANALYTICAL APPROACH

Temporal trends and pretransplant correlates of parathyroidectomy and cinacalcet use were assessed using proportional hazards models and multivariable Poisson regression, respectively.

RESULTS

The inclusion criteria were met by 30,127 patients, of whom 10,707 used cinacalcet before transplant, 551 underwent posttransplant parathyroidectomy, and 5,413 filled≥1 prescription for cinacalcet. The rate of posttransplant parathyroidectomy was stable over time. By contrast, cinacalcet use increased during the period studied. Long dialysis vintage and pretransplant cinacalcet use were strongly associated with posttransplant parathyroidectomy and cinacalcet use. Roughly 1 in 4 patients were hospitalized within 90 days of posttransplant parathyroidectomy, with hypocalcemia-related diagnoses being the most common complication. Parathyroidectomy (vs cinacalcet initiation) was not associated with an increase in acute kidney injury.

LIMITATIONS

We lacked access to laboratory data to help assess the severity of secondary/tertiary hyperparathyroidism. The cohort was limited to Medicare beneficiaries.

CONCLUSIONS

Almost one-fifth of our study cohort was treated with parathyroidectomy and/or cinacalcet. Further studies are needed to establish the optimal treatment for posttransplant hyperparathyroidism.

Topics: Humans; Aged; United States; Cinacalcet; Calcimimetic Agents; Kidney Transplantation; Parathyroidectomy; Retrospective Studies; Medicare; Hyperparathyroidism, Secondary; Parathyroid Hormone; Calcium; Kidney Failure, Chronic

PubMed: 36162617
DOI: 10.1053/j.ajkd.2022.07.015