Ethnicity evaluation of ferric pyrophosphate citrate among Asian and Non-Asian populations: a population pharmacokinetics analysis.

PURPOSE: To evaluate the potential ethnic differences of ferric pyrophosphate citrate (FPC, Triferic) in healthy subjects and patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) and identify covariates that may influence pharmacokinetics (PK) of FPC. METHODS: Data were collected from 2 Asian and 4 non-Asian clinical studies involving healthy subjects and CKD-5HD patients. Three population PK models were developed: M1 for intravenous (IV) administration of FPC in healthy subjects; M2 for dialysate administration of FPC in CKD-5HD patients; M3 for pre-dialyzer administration of FPC in CKD-5HD patients. All the models were fitted to concentration versus time data of FPC using the nonlinear mixed effect approach with the NONMEM® program. All statistical analyses were performed using SAS version 9.4. RESULTS: In total, 26 Asians and 65 non-Asians were included in the final model analysis database. Forty healthy subjects were administered FPC via intravenous (IV) route and 51 patients with CKD-5HD via dialysate (N = 50) and pre-dialyzer blood circuit administration (N = 51). The PK parameters of FPC IV were similar. The population PK model showed good parameter precision and reliability as shown by model evaluation, and no relevant influence of ethnicity on PK parameters was observed. In healthy subjects, the maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) decreased with increase in lean body mass (LBM) and the average serum total iron at 6 h before the baseline period (Feav), whereas, in both patient populations, Cmax and AUC decreased with increase in LBM and decrease in Febaseline. Other factors such as gender, age, Feav, and ethnicity had no influence on PK exposures in patients. The influence of LBM on PK exposures in patients was smaller than that in healthy subjects (ratio of AUC0-24 for the 5th [68 kg] and 95th [45 kg] patient's LBM was almost 1). The influence of Feav and LBM on PK exposures was < 50%. CONCLUSION: The population pharmacokinetics model successfully described the PK parameters of FPC in healthy subjects and CKD-5HD patients and were comparable between Asian and non-Asian populations.

Ferric pyrophosphate citrate for parenteral administration of maintenance iron: structure, mechanism of action, clinical efficacy and safety.

Anemia is a common complication in patients with hemodialysis-dependent chronic kidney disease (HDD-CKD). Anemia is principally the result of erythropoietin deficiency, inflammation, and iron deficiency. High molecular weight iron oxide nanoparticles (IONP) are routinely administered intravenously to replace iron losses and, although effective, there are lingering concerns about possible safety issues. Ferric pyrophosphate citrate (FPC, Triferic, Triferic AVNU [Triferic and Triferic AVNU are the proprietary name for ferric pyrophosphate citrate. Triferic and Triferic AVNU are registered trademarks of Rockwell medical Inc.]) is a complex iron salt that donates iron directly to plasma transferrin. FPC is devoid of any carbohydrate moiety and is administered via the dialysate or intravenously during each hemodialysis session to replace iron and maintain hemoglobin. Controlled clinical trials of up to 48 weeks in duration have demonstrated the efficacy of regular administration of dialysate FPC for maintaining hemoglobin levels and iron balance in HDD-CKD patients. Clinical data also suggest that dialysate FPC may reduce the dose requirements for and use of erythropoiesis-stimulating agents and IONPs in HDD-CKD patients. Safety data from clinical studies and post-marketing surveillance show that FPC is well tolerated and not associated with an increased risk of infection, inflammation, iron overload, or serious hypersensitivity reactions. FPC represents an effective and well-tolerated choice for iron replacement and maintenance of hemoglobin in the long-term management of HDD-CKD patients.

Pharmacokinetics and Safety of Ferric Pyrophosphate Citrate in Chinese Subjects with and without Hemodialysis-Dependent Stage 5 Chronic Kidney Disease.

BACKGROUND AND OBJECTIVE: Anemia caused by iron depletion is common in patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) patients. To maintain the iron levels, external administration of iron is essential. Ferric pyrophosphate citrate (FPC) is a novel, water-soluble complex iron salt. The present study was conducted to evaluate the pharmacokinetic (PK) parameters and safety of FPC in adult healthy Chinese subjects and patients with CKD-5HD. METHODS: Two open-label, single-center studies were conducted in healthy subjects and patients with CKD-5HD. Healthy subjects received a single intravenous dose of 6.5 mg FPC solution, while CKD-5HD patients were randomized to two different sequences of FPC administration at two sequential hemodialysis (HD) treatments (dose 1 and dose 2). Patients received 27.2 mg of FPC at a dialysate concentration of 95 µg/L for 4 h or a single 6.5 mg dose of FPC administered intravenously via the pre-dialyzer blood circuit. The primary objective was to determine the PK parameters of total serum iron (Fetot), while the secondary objective was the safety of the FPC solution. PK parameters were calculated using Phoenix WinNonlin 8.1 and other parameters were analyzed using SAS 9.4 software. Comparison between HD dose 2 and HD dose 1 was performed using the Wilcoxon rank-sum test and analysis of variance (ANOVA). RESULTS: A total of 14 healthy subjects with a mean age of 30.8 ± 5.92 years and 12 HD patients with a mean age of 54.3 ± 16.47 years were included. In healthy subjects, the peak serum concentration was reached at the end of infusion of FPC, with an adjusted mean maximum concentration (Cmax,) of 33.46 ± 4.83 µmol/L at a mean time to reach Cmax (Tmax) of 4.09 ± 0.19 h. In patients with CKD-5HD, the adjusted mean Cmax of HD dose 2 was 25.37 ± 4.30 µmol/L at a Tmax, of 3.09 ± 0.32 h, whereas the Cmax, of HD dose 1 was 24.59 ± 4.77 µmol/L at a Tmax, of 3.96 ± 0.26 h. The Fetot concentration-time curves were observed to be similar for both administration methods (HD doses 1 and 2), while the PK parameters differed significantly for Tmax (p = 0.001; baseline correction) and area under the concentration-time curve from time zero to time t (AUCt) [p = 0.031 for cycle variance; without baseline correction] between HD doses 1 and 2. The geometric mean ratios (HD dose 1/HD dose 2) for Cmax and AUCt were within the 85-125% range (Cmax 96.56%; AUCt 96.07%). A total of three and two incidences of adverse events were reported in healthy subjects and patients with CKD-5HD, respectively. CONCLUSION: FPC showed a good PK and safety profile and hence can be used as maintenance therapy for patients with CKD-5HD by choosing a better method of administration based on clinical feasibility and requirement. CLINICAL TRIAL REGISTRATION: CTR20181113 and CTR20181119.

Pharmacokinetics and Safety of Intravenous Ferric Pyrophosphate Citrate: Equivalence to Administration via Dialysate.

Ferric pyrophosphate citrate (FPC) is indicated to maintain hemoglobin in patients with stage 5 hemodialysis-dependent chronic kidney disease on chronic hemodialysis by addition to the dialysate. An intravenous (IV) FPC presentation containing 6.75 mg of iron in 4.5 mL was developed. The objective was to establish the equivalence of iron delivery via dialysate and IV infusion using a pharmacokinetic approach. An open-label, randomized, multiple-period, single-dose, crossover study was conducted in 27 patients with CKD-5HD. Each patient received (1) a basal iron profile over 12 hours, (2) FPC 6.75 mg Fe IV predialyzer, (3) FPC 6.75 mg Fe IV postdialyzer, and (4) FPC 2 µM (110 µg Fe/L of hemodialysate). Serum and plasma iron was analyzed for total Fe and transferrin bound iron (TBI). Equivalence was determined by comparing maximum observed concentration and area under the concentration-time curve from time 0 to the last observation of 110 µg Fe/L of hemodialysate (reference) and test treatments Fe predialyzer and postdialyzer iron profiles. The main outcome measure was the measurement of bioequivalence between the reference and test treatments. Bioequivalence parameters showed that infusion of FPC iron IV, predialyzer and postdialyzer delivered equivalent iron as via hemodialysate. The increment in serum total Fe from predialysis to postdialysis was the same as observed in the long-term clinical studies of FPC. FPC IV was well tolerated. IV infusion of 6.75 mg iron as FPC during 3 hours of HD delivers an equivalent amount of iron as when Triferic is delivered via hemodialysate. The IV presentation of FPC extends the ability to provide FPC iron to all patients receiving hemodialysis or hemodiafiltration.

Physicochemical characterization of ferric pyrophosphate citrate.

Iron deficiency is a significant health problem across the world. While many patients benefit from oral iron supplements, some, including those on hemodialysis require intravenous iron therapy to maintain adequate iron levels. Until recently, all iron compounds suitable for parenteral administration were colloidal iron-carbohydrate conjugates that require uptake and processing by macrophages. These compounds are associated with variable risk of anaphylaxis, oxidative stress, and inflammation, depending on their physicochemical characteristics. Ferric pyrophosphate citrate (FPC) is a novel iron compound that was approved for parenteral administration by US Food and Drug Administration in 2015. Here we report the physicochemical characteristics of FPC. FPC is a noncolloidal, highly water soluble, complex iron salt that does not contain a carbohydrate moiety. X-ray absorption spectroscopy data indicate that FPC consists of iron (III) complexed with one pyrophosphate and two citrate molecules in the solid state. This structure is preserved in solution and stable for several months, rendering it suitable for pharmaceutical applications in solid or solution state.

Ferric pyrophosphate citrate: interactions with transferrin.

There are several options available for intravenous application of iron supplements, but they all have a similar structure:-an iron core surrounded by a carbohydrate coating. These nanoparticles require processing by the reticuloendothelial system to release iron, which is subsequently picked up by the iron-binding protein transferrin and distributed throughout the body, with most of the iron supplied to the bone marrow. This process risks exposing cells and tissues to free iron, which is potentially toxic due to its high redox activity. A new parenteral iron formation, ferric pyrophosphate citrate (FPC), has a novel structure that differs from conventional intravenous iron formulations, consisting of an iron atom complexed to one pyrophosphate and two citrate anions. In this study, we show that FPC can directly transfer iron to apo-transferrin. Kinetic analyses reveal that FPC donates iron to apo-transferrin with fast binding kinetics. In addition, the crystal structure of transferrin bound to FPC shows that FPC can donate iron to both iron-binding sites found within the transferrin structure. Examination of the iron-binding sites demonstrates that the iron atoms in both sites are fully encapsulated, forming bonds with amino acid side chains in the protein as well as pyrophosphate and carbonate anions. Taken together, these data demonstrate that, unlike intravenous iron formulations, FPC can directly and rapidly donate iron to transferrin in a manner that does not expose cells and tissues to the damaging effects of free, redox-active iron.

Pharmacokinetics of ferric pyrophosphate citrate administered via dialysate and intravenously to pediatric patients on chronic hemodialysis.

BACKGROUND: Iron deficiency is a common cause of anemia in pediatric patients with hemodialysis-dependent chronic kidney disease (CKD-5HD). Ferric pyrophosphate citrate (FPC, Triferic®) donates iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Administration of FPC via dialysate or intravenously (IV) may provide a suitable therapeutic option to current IV iron preparations for these patients. METHODS: The pharmacokinetics and safety of FPC administered via dialysate and IV to patients aged < 6 years (n = 3), 6 to < 12 years (n = 4), and 12 to <18 years (n = 15) were investigated in a multicenter, open-label, two-period, single-dose study. FPC (0.07 mg iron/kg) was infused IV into the venous blood return line during hemodialysis session no. 1. FPC iron was added to bicarbonate concentrate to deliver 2 µM (110 µg/L) iron via dialysate during hemodialysis session no. 2. RESULTS: Mean serum total iron concentrations peaked 3 to 4 h after administration via dialysate and 2 to 4 h after IV administration and returned to baseline by 10 h after the start of hemodialysis for both routes. Iron exposure was greater after administration via dialysate than after IV administration. The absolute amount of absorbed iron after administration via dialysate roughly doubled with increasing age, but the weight-normalized amount of absorbed iron was relatively constant across age groups (~ 0.06-0.10 mg/kg). FPC was well tolerated in the small number of patients studied. CONCLUSIONS: FPC iron can be administered to pediatric patients with CKD-5HD via dialysate or by the IV route. Further study of FPC administered to maintain hemoglobin concentration is indicated.

Pharmacokinetics of Ferric Pyrophosphate Citrate, a Novel Iron Salt, Administered Intravenously to Healthy Volunteers.

Ferric pyrophosphate citrate (Triferic) is a water-soluble iron salt that is administered via dialysate to maintain iron balance and hemoglobin in hemodialysis patients. This double-blind, randomized, placebo-controlled, single-, ascending-dose study was conducted to evaluate the pharmacokinetics and safety of intravenous ferric pyrophosphate citrate in 48 healthy iron-replete subjects (drug, n = 36; placebo, n = 12). Single doses of 2.5, 5.0, 7.5, or 10 mg of ferric pyrophosphate citrate or placebo were administered over 4 hours, and single doses of 15 or 20 mg of ferric pyrophosphate citrate or placebo were administered over 12 hours via intravenous infusion. Serum total iron (sFetot ), transferrin-bound iron (TBI), hepcidin-25, and biomarkers of oxidative stress and inflammation were determined using validated assays. Marked diurnal variation in sFetot was observed in placebo-treated subjects. Concentrations of sFetot and TBI increased rapidly after drug administration, with maximum serum concentrations (Cmax ) reached at the end of infusion. Increases in baseline-corrected Cmax and area under the concentration-time curve from 0 to the time of the last quantifiable concentration (AUC0-t ) were dose proportional up to 100% transferrin saturation. Iron was rapidly cleared (apparent terminal phase half-life 1.2-2 hours). No significant changes from baseline in serum hepcidin-25 concentration were observed at end of infusion for any dose. Biomarkers of oxidative stress and inflammation were unaffected. Intravenous doses of ferric pyrophosphate citrate were well tolerated. These results demonstrate that intravenous ferric pyrophosphate citrate is rapidly bound to transferrin and cleared from the circulation without increasing serum hepcidin levels or biomarkers of oxidative stress or inflammation.

Ferrous iron content of intravenous iron formulations.

The observed biological differences in safety and efficacy of intravenous (IV) iron formulations are attributable to physicochemical differences. In addition to differences in carbohydrate shell, polarographic signatures due to ferric iron [Fe(III)] and ferrous iron [Fe(II)] differ among IV iron formulations. Intravenous iron contains Fe(II) and releases labile iron in the circulation. Fe(II) generates toxic free radicals and reactive oxygen species and binds to bacterial siderophores and other in vivo sequestering agents. To evaluate whether differences in Fe(II) content may account for some observed biological differences between IV iron formulations, samples from multiple lots of various IV iron formulations were dissolved in 12 M concentrated HCl to dissociate and release all iron and then diluted with water to achieve 0.1 M HCl concentration. Fe(II) was then directly measured using ferrozine reagent and ultraviolet spectroscopy at 562 nm. Total iron content was measured by adding an excess of ascorbic acid to reduce Fe(III) to Fe(II), and Fe(II) was then measured by ferrozine assay. The Fe(II) concentration as a proportion of total iron content [Fe(III) + Fe(II)] in different lots of IV iron formulations was as follows: iron gluconate, 1.4 and 1.8 %; ferumoxytol, 0.26 %; ferric carboxymaltose, 1.4 %; iron dextran, 0.8 %; and iron sucrose, 10.2, 15.5, and 11.0 % (average, 12.2 %). The average Fe(II) content in iron sucrose was, therefore, ≥7.5-fold higher than in the other IV iron formulations. Further studies are needed to investigate the relationship between Fe(II) content and increased risk of oxidative stress and infections with iron sucrose.

Ferric pyrophosphate citrate administered via dialysate reduces erythropoiesis-stimulating agent use and maintains hemoglobin in hemodialysis patients.

Ferric pyrophosphate citrate (FPC) is a water-soluble iron salt administered via dialysate to supply iron directly to transferrin. The PRIME study tested whether treatment with FPC could reduce prescribed erythropoiesis-stimulating agent (ESA) use and maintain hemoglobin in hemodialysis patients. This 9-month, randomized, placebo-controlled, double-blind, multicenter clinical study included 103 patients undergoing hemodialysis 3-4 times weekly. The FPC group received dialysate containing 2 µmol/l of iron. The placebo group received standard dialysate. A blinded central anemia management group facilitated ESA dose adjustments. Intravenous iron was administered according to the approved indication when ferritin levels fell below 200 µg/l. The primary end point was the percentage change from baseline in prescribed ESA dose at end of treatment. Secondary end points included intravenous iron use and safety. At the end of treatment, there was a significant 35% reduction in prescribed ESA dose in FPC-treated patients compared with placebo. The FPC patients used 51% less intravenous iron than placebo. Adverse and serious adverse events were similar in both groups. Thus, FPC delivered via dialysate significantly reduces the prescribed ESA dose and the amount of intravenous iron needed to maintain hemoglobin in chronic hemodialysis patients.

Ferric pyrophosphate citrate (Triferic™) administration via the dialysate maintains hemoglobin and iron balance in chronic hemodialysis patients.

BACKGROUND: Administration of ferric pyrophosphate citrate (FPC, Triferic™) via hemodialysate may allow replacement of ongoing uremic and hemodialysis-related iron losses. FPC donates iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. METHODS: Two identical Phase 3, randomized, placebo-controlled trials (CRUISE 1 and 2) were conducted in 599 iron-replete chronic hemodialysis patients. Patients were dialyzed with dialysate containing 2 µM FPC-iron or standard dialysate (placebo) for up to 48 weeks. Oral or intravenous iron supplementation was prohibited, and doses of erythropoiesis-stimulating agents were held constant. The primary efficacy end point was the change in hemoglobin (Hgb) concentration from baseline to end of treatment (EoT). Secondary end points included reticulocyte hemoglobin content (CHr) and serum ferritin. RESULTS: In both trials, Hgb concentration was maintained from baseline to EoT in the FPC group but decreased by 0.4 g/dL in the placebo group (P < 0.001, combined results; 95% confidence interval [CI] 0.2-0.6). Placebo treatment resulted in significantly larger mean decreases from baseline in CHr (-0.9 pg versus -0.4 pg, P < 0.001) and serum ferritin (-133.1 µg/L versus -69.7 µg/L, P < 0.001) than FPC treatment. The proportions of patients with adverse and serious adverse events were similar in both treatment groups. CONCLUSIONS: FPC delivered via dialysate during hemodialysis replaces iron losses, maintains Hgb concentrations, does not increase iron stores and exhibits a safety profile similar to placebo. FPC administered by hemodialysis via dialysate represents a paradigm shift in delivering maintenance iron therapy to hemodialysis patients.

Comparison of dietary phosphate absorption after single doses of lanthanum carbonate and sevelamer carbonate in healthy volunteers: a balance study.

BACKGROUND: Lanthanum carbonate and sevelamer carbonate are noncalcium phosphate binders used to treat hyperphosphatemia in patients with chronic kidney disease. This is the first study to compare phosphate absorption from a standardized meal ingested with a typical clinical dose of these binders. STUDY DESIGN: Randomized open-label crossover study. SETTINGS & PARTICIPANTS: Healthy volunteers were confined to a clinical research center during 4 study periods. Of 31 volunteers randomly assigned, 19 completed all treatments and 18 were analyzed in the pharmacodynamic set (1 was excluded because of vomiting). INTERVENTION: Participants were assigned in random order to meal alone, meal plus lanthanum carbonate (1 tablet containing 1,000 mg of elemental lanthanum), and meal plus sevelamer carbonate (three 800-mg tablets). The gastrointestinal tract was cleared, the meal was ingested (± treatment), and rectal effluent was collected. In a fourth period, volunteers repeated the study procedures while fasting. OUTCOMES: The primary end point, net phosphate absorption, was analyzed using a mixed-effect linear model. MEASUREMENTS: Phosphorus content of effluent and duplicate meal samples were measured using inductively coupled plasma-optical emission spectroscopy. RESULTS: The standard meal contained ∼375 mg of phosphate, 75% of which was absorbed (net absorption, 281.7 ± 14.1 mg [adjusted mean ± standard error]). Lanthanum carbonate decreased net phosphate absorption by 45% (net absorption, 156.0 ± 14.2 mg) compared with 21% (net absorption, 221.8 ± 14.1 mg) for sevelamer carbonate (P < 0.001). Lanthanum carbonate bound 135.1 ± 12.3 mg of phosphate, whereas sevelamer carbonate bound 63.2 ± 12.3 mg, a 71.9-mg difference (95% CI, 40.0-103.8; P < 0.001). Per tablet, this equates to 135 mg of phosphate bound with lanthanum carbonate versus 21 mg with sevelamer carbonate. LIMITATIONS: A single-dose study. CONCLUSIONS: In healthy volunteers, 1,000 mg of lanthanum carbonate decreased phosphate absorption by 45% compared with a 21% decrease with 2,400 mg of sevelamer carbonate.

Hyperphosphatemia of chronic kidney disease.

Observational studies have determined hyperphosphatemia to be a cardiovascular risk factor in chronic kidney disease. Mechanistic studies have elucidated that hyperphosphatemia is a direct stimulus to vascular calcification, which is one cause of morbid cardiovascular events contributing to the excess mortality of chronic kidney disease. This review describes the pathobiology of hyperphosphatemia that develops as a consequence of positive phosphate balance in chronic kidney disease and the mechanisms by which hyperphosphatemia acts on neointimal vascular cells that are stimulated to mineralize in chronic kidney disease. The characterization of hyperphosphatemia of chronic kidney disease as a distinct syndrome in clinical medicine with unique disordered skeletal remodeling, heterotopic mineralization and cardiovascular morbidity is presented.

A randomized, double-blind, placebo-controlled, parallel-group study of methylphenidate transdermal system in pediatric patients with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and safety of methylphenidate transdermal system compared with placebo, using osmotic-release oral system (OROS) methylphenidate as a reference therapy. METHOD: We conducted a 7-week, randomized, double-blind, double-dummy, placebo-controlled trial in children diagnosed with attention-deficit/hyperactivity disorder by DSM-IV-TR criteria, within a community setting. The study was conducted from August 2004 to February 2005. Participants were randomly assigned to 1 of 3 treatments: methylphenidate transdermal system patch plus placebo capsule (N = 100), OROS methylphenidate capsule plus placebo patch (N = 94), or placebo capsule plus placebo patch (N = 88). Over 5 weeks, once-daily doses were optimized using 10-, 15-, 20-, and 30-mg methylphenidate transdermal system patches (9-hour wear time) or 18-, 27-, 36-, and 54-mg OROS methylphenidate capsules. Thereafter, optimal treatment doses were maintained for 2 weeks with blinded ratings of attention, behavior, and academic performance occurring at the end of each week. The primary efficacy measure was the clinician-rated ADHD Rating Scale-Version IV (ADHD-RS-IV). Additional measures included teacher, parent, and other clinician rating scales. Safety and tolerability were assessed throughout the study. RESULTS: The mean change from baseline in ADHD-RS-IV scores was greater for participants receiving methylphenidate transdermal system and OROS methylphenidate treatments compared with placebo (p < .0001). Similar results were observed for parent and teacher rating scales. More participants receiving active treatments compared with placebo were rated as improved by clinicians and parents (p < .0001). Adverse events were generally mild or moderate in intensity, and the most common included decreased appetite, nausea, vomiting, and insomnia. CONCLUSIONS: The results of this study suggest that the methylphenidate transdermal system is an efficacious treatment option for children with attention-deficit/hyperactivity disorder. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00444574.

Pharmacokinetics and pharmacodynamics of epoetin delta in two studies in healthy volunteers and two studies in patients with chronic kidney disease.

BACKGROUND: Epoetin delta, unlike recombinant erythropoietins, is produced in a human cell line and therefore has a human-type glycosylation profile. OBJECTIVES: The pharmacokinetics of epoetin delta were examined in 2 studies in healthy volunteers and 2 studies in patients with chronic kidney disease. METHODS: In study 1, 21 healthy men were randomized to receive epoetin delta 15, 40, or 100 IU/kg IV tiw or placebo for 4 weeks. In study 2, an open-label, cross-over study, 32 healthy volunteers were randomized to receive single doses of epoetin delta 75 IU/kg IV or SC. In study 3, 40 patients receiving hemodialysis were withdrawn from epoetin alfa and randomized to receive epoetin delta or epoetin alfa 50 or 100 IU/kg tiw for 4 weeks. Study 4 was a single-dose study comparing epoetin delta 150 and 300 IU/kg IV or SC in 28 hemodialysis patients. RESULTS: In study 1, after repeated dosing (day 24) in healthy men, mean C(max) values ranged from 219.9 to 1793.0 enzyme-linked immunosorbent assay units (EU)/L; AUC from 827 to 9318 h x EU/L; C1 from 0.014 to 0.024 L/h per kg; Vd from 0.067 to 0.076 L/kg; and t(1/2) from 2.23 to 3.35 hours. There was evidence of a dose-dependent effect of epoetin delta on hemoglobin levels and hematocrit, with doses of 40 and 100 IU/kg associated with significant increases compared with 15 IU/kg (P < 0.001 for dose trend). The only adverse event occurring in > or = 10% of healthy individuals in study 1 was headache (1 [20.0%] in the epoetin delta 15 IU-kg group, 3 [60.0%] in the epoetin delta 100-IU/kg group, 2 [33.3%] in the placebo group). In study 2 in healthy volunteers, mean values for epoetin delta 75 IU/kg IV were 1771 EU/L for C(max), 10,632 h x EU/L for AUC, 0.010 L/h per kg for Cl, 0.074 L/kg for Vd, and 5.12 hours for t(1/2); the corresponding values for epoetin delta 75 IU/kg SC were 113 EU/L, 3231 h x EU/L, 0.035 L/h per kg, 0.760 L/kg, and 14.90 hours. The serum epoetin delta concentration peaked after 10.9 hours with subcutaneous administration. The most common adverse event in study 2 was back pain (10 [31.3%] individuals). In study 3 in patients receiving hemodialysis, mean values for C(max) and AUC with a single dose of epoetin delta 50 IU/kg were 1103 EU/L and 10,896 h x EU/L, respectively, and with the corresponding dose of epoetin alfa were 1354 EU/L and 9957 h x EU/L. Values for the 100-IU/kg doses were approximately double those for the 50-IU/kg doses. Values for Cl, Vd, and t(1/2) were numerically similar for epoetin delta and epoietin alfa across doses. Epoetin delta 100 IU/kg was associated with a numerically greater rate of increase in hemoglobin compared with the 50-IU/kg dose (mean, 0.025 vs -0.004, respectively); the results were similar for epoetin alfa (0.029 vs -0.001). The difference between epoetin alfa and epoetin delta was not statistically significant. The most common adverse events were related to edema (peripheral edema: 60%/50% for epoetin delta 50/100 IU/kg and 60%/60% for epoetin alfa 50/100 IU/kg; facial edema: 30%/30% and 50%/70%, respectively; generalized edema: 50%/30% and 40%/40%). In study 4 in patients receiving hemodialysis, mean C(max) values with epoetin delta 150 and 300 IU/kg IV were 3257 and 4770 EU/L, respectively; the corresponding mean values were 36,208 and 77,736 h x EU/L for AUC, 0.007 and 0.005 L/h per kg for Cl; 0.097 L/kg for Vd in both groups; and 9.9 and 13.2 hours for t(1/2). With epoetin delta 150 and 300 IU/kg SC, the respective values were 162.2 and 467.7 EU/L, 9547 and 27,888 h x EU/L, 0.026 and 0.020 L/h per kg, 1.28 and 0.78 L/kg, and 33.1 and 27.8 hours. The only adverse event occurring in > or = 10% of subjects was headache (2 [40.0%] in the epoetin delta 150-IU/kg IV group, 3 [50.0%] in the epoetin delta 300-IU/kg SC group). No neutralizing anti-erythropoietin antibodies were detected in any individual. The bioavailability of subcutaneous epoetin delta is approximately 30%, and concentrations peak later and decline more slowly than with intravenous injection. Pharmacokinetic parameters in hemodialysis patients were similar to those in healthy individuals, although AUC and t(1/2) were numerically higher (by 49% and 34%, respectively). CONCLUSIONS: These studies in healthy volunteers and patients with chronic kidney disease indicate that the pharmacokinetics of epoetin delta are dose dependent but nonlinear, leading to dose-dependent increases in hemoglobin levels. The pharmacodynamic response to epoetin delta appeared to be as expected for an epoetin.

Epoetin delta, erythropoietin produced in a human cell line, in the management of anaemia in predialysis chronic kidney disease patients.

OBJECTIVE: To demonstrate safety and efficacy of epoetin delta for the management of anaemia in predialysis patients with chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: This was a multicentre, open-label, uncontrolled study with predialysis CKD patients who had previously received subcutaneous epoetin therapy. Patients were switched to epoetin delta from their previous therapy, at an identical dose. Dose was subsequently titrated to maintain haemoglobin at 10.0-12.0 g/dL. Study duration was 52 weeks. MAIN OUTCOME MEASURES: The primary endpoint was average haemoglobin levels over Weeks 12, 16, 20 and 24. Secondary analyses were performed on the proportion of patients with haemoglobin and haematocrit levels over preset target levels, haemoglobin and haematocrit levels through to study end and dosing levels. RESULTS: Haemoglobin levels were maintained at 11.3 +/- 1.2 g/dL over Weeks 12-24. Over 80% of the haemoglobin measurements and 95% of the haematocrit measurements were above the predefined target level (haemoglobin > or = 10 g/dL; haematocrit > or = 30%). Weekly dose levels did not change significantly over the course of the trial. Epoetin delta was well tolerated, with adverse events occurring at frequencies expected for this patient population; no patient developed neutralizing anti-erythropoietin antibodies. CONCLUSIONS: Epoetin delta was an effective and well-tolerated agent for the management of anaemia in a subgroup of predialysis CKD patients.

Epoetin delta is effective for the management of anaemia associated with chronic kidney disease.

OBJECTIVE: To demonstrate the efficacy and safety of epoetin delta for the treatment of anaemia in dialysis patients with chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: This was a 12-week, randomized, double-blind, active-comparator study. CKD patients who were naïve to epoetin treatment and had haemoglobin < 10 g/dL were randomized to epoetin delta 15, 50, 150, or 300 IU/kg or epoetin alfa 50 IU/kg. Patients initially entered a correction phase until they recorded haemoglobin of > or = 11.5 g/dL for two consecutive weekly measurements or one haemoglobin measurement of > or = 13 g/dL (correction success). A maintenance phase followed where the dose was adjusted to maintain haemoglobin > or = 10.5 g/dL. Maintenance success was defined as haemoglobin > 10.5 g/dL at Week 12. Total success was defined as achieving maintenance and correction success. MAIN OUTCOME MEASURES: The primary objective was to demonstrate that the proportion of patients achieving total success was greater in the pooled 150 IU/kg and 300 IU/kg groups compared with the 15 IU/kg dose group. RESULTS: Total success was achieved in 55.6% of patients in the pooled highest epoetin delta group compared with 4.5% in the lowest dose group. There was no significant difference in total success for the epoetin delta and epoetin alfa 50 IU/kg groups. Significant increases in haemoglobin and haematocrit levels were observed in the 150 and 300 IU/kg dose groups. Adverse events occurred at frequencies expected for this patient group. CONCLUSIONS: Epoetin delta was effective in increasing haemoglobin levels in patients with baseline haemoglobin of < 10 g/dL.