An Initial Low-Dose Etelcalcetide Dosing Strategy in Hemodialysis Patients With Moderate Secondary Hyperparathyroidism is Effective and Cost-Saving.
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SUBMITTER: Carta A
PROVIDER: S-EPMC10850993 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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An Initial Low-Dose Etelcalcetide Dosing Strategy in Hemodialysis Patients With Moderate Secondary Hyperparathyroidism is Effective and Cost-Saving.
Carta Andrea A Tedesco Martina M Mescia Federica F Manenti Chiara C Lucca Bernardo B Verzeletti Federica F Guerini Alice A Terni Federica Gaia FG Zubani Roberto R Guerini Simona S Valzorio Brunella B Jeannin Guido G Carli Orsola O Camerini Corrado C Possenti Stefano S Gaggia Paola P Alberici Federico F
Kidney international reports 20231115 2
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Project description:IntroductionCalcimimetics improve parameters of secondary hyperparathyroidism (sHPT) but are mostly initiated when patients have severe disease, potentially limiting effectiveness. We evaluated the effects of etelcalcetide on lowering intact parathyroid hormone, calcium, and phosphate at different disease severity levels.MethodsThis analysis examined data from 2 parallel, phase 3, randomized, placebo-controlled, 26-week trials conducted in 1023 adult (≥18 years old) patients with sHPT on maintenance hemodialysis. Etelcalcetide effects by baseline intact parathyroid hormone stratum (<600, 600-1000, and >1000 ng/l) on mean percentage change in intact parathyroid hormone; changes in calcium and phosphate; and achieving serum intact parathyroid hormone ≤300 ng/l, phosphate <1.78 mmol/l, and both combined, were assessed.ResultsEtelcalcetide reduced serum intact parathyroid hormone by a similar percentage across baseline strata. A similar proportion achieved >30% intact parathyroid hormone reduction across strata for the etelcalcetide arms. Parathyroid hormone increased modestly in each placebo-group stratum, most prominently in the lowest stratum. Serum calcium and phosphate concentrations decreased across strata in etelcalcetide-treated patients, with the most pronounced reductions in patients with highest baseline parathyroid hormone. However, the proportion of patients achieving parathyroid hormone, phosphate, and both targets was highest in the lowest baseline parathyroid hormone stratum, where etelcalcetide dose requirements were lowest. Etelcalcetide dose requirement was lowest among patients in the lowest intact parathyroid hormone stratum.ConclusionEtelcalcetide effectively lowered serum intact parathyroid hormone, calcium, and phosphate, irrespective of the severity of secondary hyperparathyroidism. The ability to achieve target goals was greatest, and dose requirement smallest, when etelcalcetide was initiated among patients with the lowest level of disease severity.
| S-EPMC6611952 | biostudies-literature
Project description:BackgroundSecondary hyperparathyroidism (sHPT), a common complication of chronic kidney disease, is characterized by elevated serum parathyroid hormone (PTH). Etelcalcetide is an intravenous calcimimetic that increases sensitivity of the calcium-sensing receptor to calcium and decreases PTH secretion. This open-label extension (OLE) trial evaluated the long-term effects of etelcalcetide for sHPT treatment in patients receiving hemodialysis.MethodsThis 52-week, multicenter, single-arm OLE enrolled patients from three parent trials: two randomized, double-blind, placebo-controlled trials and one open-label, single-arm, 'switch' study from cinacalcet to etelcalcetide. The primary endpoint was to investigate the nature, frequency, severity and relation to treatment of all adverse events (AEs) reported throughout the trial. Secondary endpoints included the proportion of patients with >30% reduction from baseline in PTH and the percentage change from baseline in PTH, albumin-corrected calcium (Ca), phosphate (P) and the calcium-phosphate product (Ca × P).ClinicalTrials.gov identifier: NCT01785875; Amgen study: 20120231.ResultsOverall, 89.8% of the patients experienced one or more treatment-emergent AE. The most common were decreased blood Ca (43.3%), diarrhea (10.8%), vomiting (10.4%) and nausea (9.6%); symptomatic hypocalcemia occurred in 3.7% of the patients. Approximately 68% of patients achieved >30% reduction in PTH, and ∼56% achieved PTH ≤300 pg/mL. Mean percent changes from baseline ranged from -25.4% to -26.1% for PTH, -8.3% to -9.1% for Ca, -3.6% to -4.1% for P and -12.0% to -12.6% for Ca × P.ConclusionsEtelcalcetide effectively lowered PTH and its effect was sustained, while no new safety concerns emerged over a 1-year treatment period.
| S-EPMC7538239 | biostudies-literature
Project description:IntroductionThe pharmacokinetics, pharmacodynamics, and safety and tolerability profile of etelcalcetide (ONO-5163/AMG 416), a novel, i.v., long-acting calcium-sensing receptor agonist, were studied in Japanese hemodialysis patients with secondary hyperparathyroidism.MethodsThis multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisted of a single dose part and a multiple dose (3 times weekly for 4 weeks) part. Major inclusion criteria were hemodialysis for at least 90 days, serum intact parathyroid hormone (iPTH) ≥ 300 pg/ml, and serum albumin-corrected Ca (cCa) ≥ 9.0 mg/dl. There were 3 single-dose cohorts (n = 6 each) randomized 2:1 to 5, 10, or 20 mg etelcalcetide or placebo, and 2 multiple-dose cohorts (n = 11 each) randomized 8:3 to 2.5 or 5 mg etelcalcetide or placebo.ResultsEtelcalcetide plasma concentration decreased rapidly after i.v. administration, generally remained stable from 24 hours postdose to the next dialysis, and then decreased by dialysis. Etelcalcetide exposure increased dose proportionally. Etelcalcetide plasma predialysis concentration reached almost steady state at week 4. A single dose of etelcalcetide dose-dependently reduced serum iPTH in 30 minutes, and the reduction reached a plateau at 1 hour that lasted until 8 hours. The percent change from baseline serum iPTH thereafter showed a trend to gradually decrease; it was still -30% or greater on day 3. Similar results were obtained at the last injection (days 27-29) of the multiple dose. The effect of the multiple dose was sustained during the interdialytic period. Etelcalcetide decreased serum cCa in a more gradual but dose-dependent and sustained manner.DiscussionEtelcalcetide dose-dependently reduced serum iPTH and serum cCa. Moreover, the effect was sustained in the interdialytic period.
| S-EPMC5678849 | biostudies-literature
Project description:BackgroundCalcimimetics 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.MethodsThis 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.ResultsOverall, 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.ConclusionsThis 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.
| S-EPMC6420005 | biostudies-literature
Project description:IntroductionEtelcalcetide, a novel calcimimetic agonist of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in chronic kidney disease patients on hemodialysis, is a d-amino acid linear heptapeptide with a d-cysteine that is linked to an l-cysteine by a disulfide bond. In addition to binding to the calcium-sensing receptor, etelcalcetide is biotransformed by disulfide exchange in whole blood to predominantly form a covalent serum albumin peptide conjugate (SAPC). Key factors anticipated to affect the pharmacokinetics and disposition of etelcalcetide in chronic kidney disease patients on hemodialysis are the drug's intrinsic dialytic properties and biotransformation kinetics.MethodsThese factors were investigated using in vitro methods, and the findings were modeled to derive corresponding kinetic rate constants.ResultsBiotransformation was reversible after incubation of etelcalcetide or SAPC in human whole blood. The rate of SAPC formation from etelcalcetide was 18-fold faster than the reverse process. Clearance of etelcalcetide by hemodialysis was rapid in the absence of blood and when hemodialysis was initiated immediately after addition of etelcalcetide to blood. Preincubation of etelcalcetide in blood for 3 hours before hemodialysis resulted in formation of SAPC and decreased its clearance due to the slow rate of etelcalcetide formation from SAPC. Etelcalcetide hemodialysis clearance was >16-fold faster than its biotransformation.DiscussionThese results indicate that etelcalcetide should be administered after hemodialysis to avoid elimination of a significant fraction of the dose.
| S-EPMC5720529 | biostudies-literature
Project description:Etelcalcetide is a novel calcimimetic in development for the treatment of secondary hyperparathyroidism (SHPT). A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed relating etelcalcetide exposures to markers of efficacy (parathyroid hormone [PTH]) and safety (calcium) using data from three clinical studies. The semimechanistic model was developed that included allosteric activation pharmacology and understanding of calcium homeostasis. The temporal profiles for all biomarkers were well described by the model. The cooperativity constant was 4.94, confirming allosteric activation mechanism. Subjects with more severe disease (higher PTH baseline) were predicted to experience less pronounced reduction in PTH (percentage change from baseline), but more reduction in calcium (Ca; percentage change from baseline). There was no evidence that dose adjustment by any covariate was needed. Model-based simulations provided quantitative support to several elements of dosing, such as starting dose, monitoring, and titration timing for registration trials.
| S-EPMC5036423 | biostudies-literature
Project description:IntroductionThe clinical trial on the Development of a treatment strategy for chronic kidney disease‒mineral and bone disorder by a mUltilateral mechanism of ETelcalcetide hydrochloride, or the DUET trial, was designed to determine the efficacy of etelcalcetide, an intravenous calcimimetic, for control of secondary hyperparathyroidism (SHPT).MethodsEligible SHPT maintenance hemodialysis patients (n = 124) were randomized (1:1:1) for inclusion in the DUET trial, a 12-week, multicenter, open-label, parallel-group study (jRCTs041180108), and assigned to either an etelcalcetide + active vitamin D group (group E+D), an etelcalcetide + oral calcium preparation group (group E+Ca), or a control group (group C). The primary endpoint was number of patients with a 50% reduction from baseline of intact parathyroid hormone (iPTH) levels, and iPTH levels ≤ 240 pg/mL at 12 weeks after start of the trial.ResultsThe proportion of patients reaching the primary endpoint (95% confidence interval [CI]) was 90.0% (76.3%-97.2%) in group E+D, 56.8% (39.5%-72.9%) in group E+Ca, and 19.5% (8.8%-34.9%) in group C. Etelcalcetide treatment led to a significant increase in the number of patients achieving the endpoint (odds ratio, 13.4; 95% CI, 5.10-35.3) on logistic regression analysis, with iPTH, corrected serum calcium, and phosphate at baseline as covariates. Significantly more patients achieved the endpoint in group E+D compared with group E+Ca (odds ratio, 6.35; 95% CI, 1.79-22.48). There were fewer hypocalcemic visits in group E+D compared with group E+Ca (P = 0.018), yet the former group was prone to hyperphosphatemia.ConclusionEtelcalcetide showed good control of iPTH for maintenance hemodialysis patients with SHPT. Active vitamin D was useful in correcting hypocalcemia, but the oral calcium preparation was superior for suppression of hyperphosphatemia.
| S-EPMC7710846 | biostudies-literature
Project description: Not available
| S-EPMC9171704 | biostudies-literature
Project description:BackgroundThe antibody-drug conjugate sacituzumab govitecan is approved for metastatic triple-negative breast cancer and has shown promising results in various other types of cancer. Its costs may limit patient access to this novel effective treatment modality.ObjectiveThe purpose of this study was to develop an evidence-based rational dosing regimen that results in targeted drug exposure within the therapeutic range while minimizing financial toxicity, to improve treatment access.Patients and methodsExposure equivalent dosing strategies were developed based on pharmacokinetic modeling and simulation by using the published pharmacokinetic model developed by the license holder. The alternative dose was based on the principle of using complete vials to prevent spillage and on the established non-linear relationship between body weight and systemic exposure. Equivalent exposure compared to the approved dosing regimen of 10 mg/kg was aimed for. Equivalent exposure was conservatively defined as calculated geometric mean ratios within the 0.9-1.11 boundaries for area under the concentration-time curve (AUC), trough concentration (Ctrough) and maximum concentration (Cmax) of the alternative dosing regimen compared to the approved dosing regimen. Since different vial sizes are available for the European Union (EU) and United States (US) market, because body weight distributions differ between these populations, we performed our analysis for both scenarios.ResultsDosing regimens of sacituzumab govitecan for the EU (< 50 kg: 400 mg, 50-80 kg: 600 mg, and > 80 kg: 800 mg) and US population (< 40 kg: 360 mg, 40-65 kg: 540 mg, 65-90 kg: 720 mg, and > 90 kg: 900 mg) were developed, based on weight bands. The geometric mean ratios for all pharmacokinetic outcomes were within the predefined equivalence boundaries, while the quantity of drug used was 21.5% and 19.0% lower for the EU and US scenarios, respectively.ConclusionsWith the alternative dosing proposal, an approximately 20% reduction in drug expenses for sacituzumab govitecan can be realized while maintaining an equivalent and more evenly distributed exposure throughout the body weight range, without notable increases in pharmacokinetic variability.
| S-EPMC11393053 | biostudies-literature
Project description:AimEnfortumab vedotin is an antibody-drug conjugate (ADC) that has been approved for locally advanced or metastatic urothelial cancer, as monotherapy and in combination with pembrolizumab, and has shown significant benefit in progression-free survival and overall survival for these patients. The economic burden of enfortumab vedotin hampers widespread patient access. The aim of this study was to develop a model-informed alternative dosing regimen that results in equivalent drug exposure while reducing the costs and prevent drug spillage.MethodsPopulation pharmacokinetic modelling was used to simulate a dosing regimen leading to equivalent exposure by using the published population pharmacokinetic model in the registration reports. The alternative dosing regimen was based on weight-bands derived from the established non-linear relationship between body weight and systemic exposure, and the usage of whole vials based on fixed doses to prevent spillage. Equivalent exposure compared to the approved body weight-based dosing regimen was defined as conservative equivalent boundaries of 90-111% for the calculated geometric mean ratios (GMRs) of area under the concentration-time curve and trough concentration.ResultsA weight-band based dosing regimen for each dose level of enfortumab vedotin was developed. The GMRs for all pharmacokinetic outcomes were within the predefined equivalence boundaries. In addition, a more even exposure distribution was observed across the body weight quartiles. The average costs savings across all dose levels and per weight-band were approximately 15%.ConclusionThe proposed alternative dosing regimen shows that drug costs and spillage of enfortumab vedotin can be reduced while maintaining an equivalent and more evenly distributed exposure in treated patients.
| S-EPMC11860999 | biostudies-literature