Safety and efficacy of ferric citrate in patients with nondialysis-dependent chronic kidney disease

PLoS One. 2017 Nov 29;12(11):e0188712. doi: 10.1371/journal.pone.0188712. eCollection 2017.

Abstract

Two randomized, placebo-controlled trials conducted in patients with nondialysis-dependent (NDD) chronic kidney disease (CKD), iron deficiency anemia, and normal or elevated serum phosphorus demonstrated that ferric citrate (FC) significantly increased hemoglobin and decreased serum phosphate concentrations. Pooling these trial results could provide a more robust evaluation of the safety and efficacy of FC in this population. We pooled results of a phase 2 (n = 149) and 3 trial (n = 233) of patients randomized and treated for up to 12 and 16 weeks, respectively. The starting dose in both trials was three 1-g (elemental iron 210 mg) tablets/day with food, up to 12 tablets/day. Doses were titrated in the phase 2 and 3 trials to lower serum phosphate concentrations to a target range (0.97-1.13 mmol/L) and to achieve a ≥10-g/L hemoglobin increase, respectively. Safety was assessed in all patients who received ≥1 dose of FC (n = 190) and placebo (n = 188). Treatment-emergent adverse events (AEs) were reported in 143 of 190 (75.3%) FC-treated and 116 of 188 (61.7%) placebo-treated patients; gastrointestinal AEs were the most frequent (94 [49.5%] vs. 52 [27.7%], respectively). Specific events reported in >5% of patients (FC vs. placebo, respectively) included discolored feces (41 [21.6%] vs. 0 [0.0%]), diarrhea (39 [20.5%] vs. 23 [12.2%]), constipation (35 [18.4%] vs. 19 [10.1%]), and nausea (18 [9.5%] vs. 8 [4.3%]). Twenty FC-treated (10.5%) and 21 placebo-treated patients (11.2%) experienced a serious AE. Two patients (1.1%) died in each group. A pooled efficacy assessment demonstrated a consistent hemoglobin rise and modest serum phosphate decline, with few excursions below the normal range. When used for treatment of patients with NDD-CKD, FC contributes to gastrointestinal AEs at higher rates than placebo, while simultaneously correcting two of the principal metabolic manifestations of CKD (iron deficiency anemia and relative hyperphosphatemia).

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anemia, Iron-Deficiency / complications
  • Anemia, Iron-Deficiency / drug therapy*
  • Dose-Response Relationship, Drug
  • Female
  • Ferric Compounds / adverse effects
  • Ferric Compounds / therapeutic use*
  • Humans
  • Kidney Failure, Chronic / complications
  • Kidney Failure, Chronic / drug therapy*
  • Male
  • Middle Aged
  • Placebos

Substances

  • Ferric Compounds
  • Placebos
  • ferric citrate

Grants and funding

GMC has served as a consultant to Akebia, Amgen, Ardea, AstraZeneca, Bristol-Myers Squibb, Gilead, Keryx, and ZS Pharma, has ownership interest in Ardelyx, Durect, Outset, PuraCath Medical, Physiowave, and Thrasos, has received research support from Amgen, Janssen, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Heart, Lung, and Blood Institute, and has received honoraria from the American Society of Nephrology. GAB has served as a consultant for Akebia, Amgen, Ardelyx, AstraZeneca, Celgene, Daiichi Sankyo, Keryx, Relypsa, Sanfit, and ZS Pharma, has ownership interest in Ardelyx and Nephroceuticals, has received research support from Keryx, and has received honoraria from Akebia, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Keryx, and Sanofi. JFN and KU are employees of Keryx and have ownership interest in Keryx. PEP has served as a consultant for Keryx, Relypsa, Sandoz, Vifor Pharma, and ZS Pharma, and has received honoraria from Keryx, Relypsa, Sandoz, and ZS Pharma. SF has served as a consultant for AstraZeneca, Keryx, Rockwell, and ZS Pharma, has received research funding from Amgen, AstraZeneca, Janssen, and ZS Pharma, and has received honoraria from AstraZeneca, Keryx, Rockwell, and ZS Pharma. The phase 2 and phase 3 clinical trials and the pooled analysis were supported by Keryx Biopharmaceuticals, Inc. Keryx provided support in the form of salaries for KU and JFN, both of whom contributed towards the design of the study and data analysis, as well as reviewing and editing of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Robert Schupp, PharmD, CMPP, of inScience Communications, Springer Healthcare (New York, NY, USA), provided editorial support, funded by Keryx Biopharmaceuticals, Inc.