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Clinical Pharmacokinetics Dec 2015The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with... (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia.
METHODS
Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site.
RESULTS
Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively.
CONCLUSIONS
A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.
Topics: Administration, Intravenous; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Female; Hematinics; Humans; Hypothermia; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Male
PubMed: 25989868
DOI: 10.1007/s40262-015-0286-y -
American Journal of Nephrology 2021Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese,... (Comparative Study)
Comparative Study Randomized Controlled Trial
INTRODUCTION
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness.
METHODS
Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18-24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated.
RESULTS
Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m2 were associated with requiring higher DA but not roxadustat doses.
DISCUSSION/CONCLUSION
The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.
Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Female; Glycine; Hematinics; Humans; Isoquinolines; Japan; Male; Middle Aged; Renal Insufficiency, Chronic
PubMed: 34628408
DOI: 10.1159/000519043 -
Clinical Journal of the American... Jan 2018The study was conducted to identify a conversion factor for switching from previous erythropoiesis-stimulating agents (ESAs) to continuous erythropoietin receptor...
BACKGROUND AND OBJECTIVES
The study was conducted to identify a conversion factor for switching from previous erythropoiesis-stimulating agents (ESAs) to continuous erythropoietin receptor activator-methoxy polyethylene glycol-epoetin beta (C.E.R.A.) and to document the efficacy and long-term safety of C.E.R.A. in pediatric patients with anemia of CKD undergoing hemodialysis.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
In this open-label, multicenter study, patients aged 6-17 years, with stable chronic anemia of CKD, undergoing hemodialysis received C.E.R.A. every 4 weeks, at a starting dose determined by previous weekly epoetin alfa/beta or darbepoetin dosing. After a 16-week dose-titration and a 4-week evaluation period, patients with stable hemoglobin could enter a 1-year optional safety extension.
RESULTS
A total of 64 patients were enrolled. A conversion factor (4 g every 4 weeks for each weekly dose of 125 IU epoetin alfa/beta or 0.55 g darbepoetin) was identified that allowed patients to maintain hemoglobin within target levels on switching to C.E.R.A. from another ESA. Using this conversion factor, the adjusted mean change in hemoglobin from baseline to evaluation was -0.09 g/dl (95% confidence interval, -0.45 to 0.26); 81% of patients maintained hemoglobin within 10.0-12.0 g/dl and 75% maintained hemoglobin within 1.0 g/dl of baseline. Results were consistent across age groups (6-11 and 12-17 years) and previous ESA. Thirty-seven patients entered the safety extension period and 17 completed 73 weeks of treatment. Most withdrawals were for kidney transplantation. A total of 70% of patients had hemoglobin within 10.0-12.0 g/dl at last observation, and 62% were within ±1.0 g/dl of baseline. Safety was similar to studies in adult patients, with no new signal detected.
CONCLUSIONS
Using a defined conversion factor, 4-weekly C.E.R.A. was efficacious in maintaining hemoglobin levels in pediatric patients with stable anemia of CKD undergoing hemodialysis, switching from maintenance treatment with epoetin alfa/beta or darbepoetin. Safety was consistent with the known C.E.R.A. safety profile in adults.
Topics: Adolescent; Age Factors; Anemia; Biomarkers; Child; Drug Administration Schedule; Drug Substitution; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome
PubMed: 29097481
DOI: 10.2215/CJN.03570417 -
Journal of Thoracic Oncology : Official... Feb 2020
Topics: Anemia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Darbepoetin alfa; Double-Blind Method; Humans; Lung Neoplasms
PubMed: 32127181
DOI: 10.1016/j.jtho.2019.11.002 -
Cancer Management and Research 2016To assess hemoglobin (Hb) outcomes and fatigue-related quality-of-life (QoL) (electronic assessment) in patients with solid tumors and symptomatic chemotherapy-induced...
PURPOSE
To assess hemoglobin (Hb) outcomes and fatigue-related quality-of-life (QoL) (electronic assessment) in patients with solid tumors and symptomatic chemotherapy-induced anemia receiving cytotoxic chemotherapy and darbepoetin alfa (DA) or another erythropoiesis-stimulating agent according to European indication.
METHODS
eAQUA was a Phase IV prospective observational study. The primary outcome (assessed in the primary analysis set [PAS]: patients receiving one or more DA dose who had baseline and week 9 assessments for Hb and QoL) was the proportion of patients receiving DA having both Hb increases ≥1 g/dL and improved QoL between baseline and week 9. Functional Assessment of Cancer Therapy-Fatigue (FACT-F) subscale scores were anchored to fatigue visual analog scale scores to determine the minimally important difference for improved QoL. Overall data/data over time are reported for the full analysis set (patients receiving one or more erythropoiesis-stimulating agent dose, n=1,158); week 9 data (ie, data relating to the primary and secondary outcomes) are reported for the PAS (n=510). Baseline and safety data are included for both the full analysis set and PAS.
RESULTS
In the PAS, 69% of patients had stage IV disease and 96% were fatigued. The minimally important difference in FACT-F change score for QoL improvement was 3.5. From baseline to week 9, 32% (95% confidence interval: 28%-36%) of patients had both improved QoL and an Hb increase ≥1 g/dL; proportions were similar across the most common tumor types. At week 9, 49% and 58% of patients had improved QoL or Hb increases ≥1 g/dL, respectively; 70% and 76% had QoL or Hb improvements between baseline and study end, respectively. In the PAS, 16% of patients required transfusions and 32% required iron supplementation. Few patients (<1%) reported adverse drug reactions.
CONCLUSION
In this study, patients with solid tumors receiving DA per European indication for symptomatic chemotherapy-induced anemia had clinically meaningful improvements in Hb and QoL.
PubMed: 26855598
DOI: 10.2147/CMAR.S88110 -
Kidney International Reports Jul 2021Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated safety and efficacy versus placebo in phase III trials in patients with...
INTRODUCTION
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated safety and efficacy versus placebo in phase III trials in patients with anemia of chronic kidney disease (CKD) who were not on dialysis (NDD).
METHODS
This was a phase III, active-controlled, multicenter, partially randomized, open-label study in Japanese patients with NDD CKD. Patients who had used recombinant human erythropoietin or darbepoetin alfa (DA) before conversion were randomized to roxadustat or DA (comparative arms). Patients who had used epoetin beta pegol before conversion were allocated to roxadustat (reference arm). The primary endpoint was change in average hemoglobin (Hb) level from baseline during the evaluation period (Weeks 18-24). Longer term efficacy and safety were evaluated in roxadustat-treated patients over 52 weeks.
RESULTS
In this study, 334 patients were randomized/allocated to receive treatment ( = 132, roxadustat [comparative]; = 131, DA [comparative]; = 71, roxadustat [reference]). The estimated difference between the roxadustat (comparative) and DA (comparative) groups in the least squares mean of change of average Hb levels of Weeks 18 to 24 from baseline was -0.07 g/dl, with the lower limit of 95% confidence interval of -0.23 g/dl, thereby confirming the noninferiority of roxadustat to DA. Common treatment-emergent adverse events (≥3% of patients in any treatment group) observed during the 24-week treatment period included nasopharyngitis, CKD, hyperkalemia, and hypertension.
CONCLUSION
Roxadustat maintained Hb within 10 to 12 g/dl in NDD CKD patients and was noninferior to DA. The safety profiles observed in this study are consistent with previous studies performed in this patient population.
PubMed: 34307976
DOI: 10.1016/j.ekir.2021.04.003 -
PloS One 2016We aimed to identify associations between erythroferrone (ERFE), a regulator of hepcidin 25, and biomarkers of erythropoiesis and iron metabolism. We also aimed to... (Comparative Study)
Comparative Study
Associations among Erythroferrone and Biomarkers of Erythropoiesis and Iron Metabolism, and Treatment with Long-Term Erythropoiesis-Stimulating Agents in Patients on Hemodialysis.
BACKGROUND
We aimed to identify associations between erythroferrone (ERFE), a regulator of hepcidin 25, and biomarkers of erythropoiesis and iron metabolism. We also aimed to determine the effects of erythropoiesis-stimulating agents (ESA), continuous erythropoietin receptor activator (CERA) and darbepoetin-α (DA) on ERFE production in patients on hemodialysis (HD).
METHODS
Blood samples were obtained from 59 patients before HD sessions on day 0 (baseline). Twenty patients who were injected with either CERA (N = 10) or DA (N = 10) at the end of the dialysis week (day 0), who had ferritin ≥ 100 ng/mL and/or transferrin saturation ≥ 20%, and hemoglobin > 9 g/dL were selected from among the 59 patients. Blood was sampled serially before HD sessions on days 3, 5, 7 from patients on DA and on the same days plus day 14 from those on CERA.
RESULTS
Levels of ERFE correlated inversely with those of hepcidin 25 and ferritin, and positively with those of soluble transferrin receptor. The hepcidin 25: ERFE ratio and hepcidin 25 levels positively correlated with ferritin levels. Levels of ERFE significantly increased from day 3 of treatment with DA and CERA and decreased by days 7 and 14, respectively. Erythropoiesis-stimulating agents concomitantly decreased levels of hepcidin 25 as those of ERFE increased.
CONCLUSION
We identified a novel association between ESA and ERFE in patients on HD. Both DA and CERA increased levels of ERFE that regulated hepcidin 25 and led to iron mobilization from body stores during erythropoiesis.
Topics: Aged; Aged, 80 and over; Anemia; Biomarkers; Cross-Sectional Studies; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Hepcidins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Peptide Hormones; Polyethylene Glycols; Prospective Studies; Receptors, Transferrin; Renal Dialysis; Reticulocyte Count; Time Factors; Transferrin
PubMed: 26978524
DOI: 10.1371/journal.pone.0151601 -
MBio Feb 2023Streptococcus pneumoniae colonizes the human nasopharynx and causes several diseases. Pneumococcal vaccines target the polysaccharide capsule and prevent most serious...
Streptococcus pneumoniae colonizes the human nasopharynx and causes several diseases. Pneumococcal vaccines target the polysaccharide capsule and prevent most serious disease, but there has been an increase in the prevalence of nonencapsulated S. pneumoniae (NESp). Previously, it was thought that a capsule was necessary to cause invasive disease. NESp strains expressing the oligopeptide transporters AliC and AliD have been isolated from patients with invasive disease. The AliC and AliD oligopeptide transporters regulate the expression of several genes, including choline binding protein AC (CbpAC) (a homolog of PspA), which aids in reducing C3b deposition. It is hypothesized that by altering CbpAC expression, AliC and AliD provide protection from classical complement-mediated clearance by reducing C-reactive protein (CRP) binding. Our study demonstrates that AliC and AliD regulate CbpAC expression in NESp and that AliD found in certain serotypes of encapsulated strains regulates PspA expression. C3b deposition was increased in the NESp Δ and encapsulated mutants in comparison to the wild type. NESp strains expressing AliC and AliD have a significant decrease in C1q and CRP deposition in comparison to the Δ Δ mutant. The complement protein C1q is required for NESp clearance in a murine model and increases opsonophagocytosis. By regulating CbpAC expression, NESp inhibits CRP binding to the bacterial surface and blocks classical complement activation, leading to greater systemic survival and virulence. Due to the increase in the prevalence of NESp, it is important to gain a better understanding of NESp virulence mechanisms that aid in establishing disease and persistence within a host by avoiding clearance by the immune system. Streptococcus pneumoniae (pneumococcus) can cause a range of diseases. Although there is a robust pneumococcal vaccination program that reduces invasive pneumococcal disease by targeting various polysaccharide capsules, there has been an increase in the isolation of nonvaccine serotypes and nonencapsulated S. pneumoniae (NESp) strains. While most studies of pneumococcal pathogenesis have focused on encapsulated strains, there is little understanding of how NESp causes disease. NESp lacks a protective capsule but contains novel genes, such as and , which have been shown to regulate the expression of numerous genes and to be required for NESp virulence and immune evasion. Furthermore, NESp strains have high transformation efficiencies and harbor resistance to multiple drugs. This could be deleterious to current treatment strategies employed for pneumococcal disease as NESp can be a reservoir of drug resistance genes. Therefore, deciphering how NESp survives within a host and facilitates disease is a necessity that will allow the fabrication of improved, broad-spectrum treatments and preventatives against pneumococcal disease. Our study provides a better understanding of NESp virulence mechanisms during host-pathogen interactions through the examination of genes directly regulated by the NESp proteins AliC and AliD.
Topics: Animals; Humans; Mice; Bacterial Proteins; Carrier Proteins; Choline; Complement C1q; Darbepoetin alfa; Membrane Transport Proteins; Pneumococcal Infections; Streptococcus pneumoniae
PubMed: 36625598
DOI: 10.1128/mbio.03325-22 -
Frontiers in Pediatrics 2018Anemia treatment in infants with advanced or chronic kidney disease (CKD) represents an important challenge to nephrologists. The use of darbepoetin alfa, a novel...
Anemia treatment in infants with advanced or chronic kidney disease (CKD) represents an important challenge to nephrologists. The use of darbepoetin alfa, a novel erythropoiesis stimulating agent, has largely replaced recombinant human erythropoietin in older children and in adults with CKD. However, studies reporting the use of darbepoetin alfa in infants below 1 year of age are rare. We report the data of three infants with advanced stage kidney failure, aged 1, 4, and 7 months, who were treated with darbepoetin alfa and followed for 18-41 months. Hemoglobin levels increased in all three patients, reaching the target levels of 10.7-12 g/dl by 11, 19, and 22 weeks respectively, without any documented adverse effects. Patients younger than 1 year of age required a larger darbepoetin alfa dosage (ranged from 1.2 to 2.9 μg/kg per month) as compared to older children. A review of the literature found only three studies using darbepoetin alfa successfully in such young infants, with similar dosage and clinical success. In these three patients with advanced kidney disease, darbepoetin alfa was effective in correcting anemia with no observed side effects. It reinforces its potential use in very young patients with advanced CKD.
PubMed: 30619793
DOI: 10.3389/fped.2018.00398 -
The Journal of Clinical Investigation Apr 2023Genetic defects of GNAS, the imprinted gene encoding the stimulatory G protein α-subunit, are responsible for multiple diseases. Abnormal GNAS imprinting causes...
Genetic defects of GNAS, the imprinted gene encoding the stimulatory G protein α-subunit, are responsible for multiple diseases. Abnormal GNAS imprinting causes pseudohypoparathyroidism type 1B (PHP1B), a prototype of mammalian end-organ hormone resistance. Hypomethylation at the maternally methylated GNAS A/B region is the only shared defect in patients with PHP1B. In autosomal dominant (AD) PHP1B kindreds, A/B hypomethylation is associated with maternal microdeletions at either the GNAS NESP55 differentially methylated region or the STX16 gene located approximately 170 kb upstream. Functional evidence is meager regarding the causality of these microdeletions. Moreover, the mechanisms linking A/B methylation and the putative imprinting control regions (ICRs) NESP-ICR and STX16-ICR remain unknown. Here, we generated a human embryonic stem cell model of AD-PHP1B by introducing ICR deletions using CRISPR/Cas9. With this model, we showed that the NESP-ICR is required for methylation and transcriptional silencing of A/B on the maternal allele. We also found that the SXT16-ICR is a long-range enhancer of NESP55 transcription, which originates from the maternal NESP-ICR. Furthermore, we demonstrated that the STX16-ICR is an embryonic stage-specific enhancer enabled by the direct binding of pluripotency factors. Our findings uncover an essential GNAS imprinting control mechanism and advance the molecular understanding of PHP1B pathogenesis.
Topics: Animals; Humans; Darbepoetin alfa; Chromogranins; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; DNA Methylation; Genomic Imprinting; Mammals
PubMed: 36853809
DOI: 10.1172/JCI167953