Comparison of the Pharmacokinetic Properties of Extended Half-Life and Recombinant Factor VIII Concentrates by In Silico Simulations.

BACKGROUND: The pharmacokinetic (PK) properties of extended half-life (EHL) factor VIII (FVIII) concentrates differ, leading to variation in the optimal dosing regimen for the individual patient. The aim of this study was to establish these PK differences for various EHL FVIII concentrates by in silico simulations. METHODS: FVIII level over time profiles of rFVIII-SC, BAY 81-8973, rFVIII-Fc, BAX 855, BAY 94-9027, and standard half-life (SHL) rFVIII concentrates were simulated for 1,000 severe hemophilia A patients during steady-state dosing of 40 IU/kg every 72 hours or dosing as advised in the summary of product characteristics (SmPC). RESULTS: Although the elimination half-life values were comparable for rFVIII-FC, BAX 855, and BAY 94-9027, a higher area under the curve (AUC; 2,779 IU/h/dL) for BAY 94-9027 was obtained. During steady-state dosing of 40 IU/kg every 72 hours, 58.5% (rFVIII-SC), 69.3% (BAY 81-8972), 89.0% (rFVIII-Fc), 83.9% (BAX 855), and 93.7% (BAY 94-9027) of the patients maintained a trough level of 1 IU/dL, compared with 56.0% for SHL rFVIII. Following dosing schemes described in the SmPC, between 51.0 and 65.4% or 23.2 and 31.1% of the patients maintained a target trough level of 1 IU/dL or 3 IU/dL, respectively. CONCLUSION: BAY 94-9027 showed the largest increase of AUC and best target attainment compared with SHL rFVIII, followed closely by BAX 855 and rFVIII-Fc. BAY 81-8973 and rFVIII-SC showed smaller PK improvements. Although our analyses increase insight into the PK of these FVIII concentrates, more studies evaluating the relation between factor levels and bleeding risk are needed.

Safety Assessment of PEGylated Alkyl Glycerides as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 60 PEGylated alkyl glycerides. PEGylated alkyl glycerides are mono-, di-, and/or triglycerides that have been modified with ethylene glycol repeat units (in the starting material form as epoxide). Most of the PEGylated alkyl glycerides are reported to function as skin-conditioning agents or surfactants. The Panel reviewed the available animal and clinical data as well as data from the 1999 report for the 5 polyethylene glycol (PEG) glyceryl cocoates and the 2012 report of PEGylated oils, to determine the safety of these ingredients. The Panel concluded these ingredients are safe in the current practices of use and concentration when formulated to be nonirritating; this conclusion supersedes the 1999 conclusion issued on 5 PEG glyceryl cocoate ingredients.

Engineering and biological assessment of double core nanoplatform for co-delivery of hybrid fluorophores to human melanoma.

We investigated new development in photodynamic therapy (PDT), aiming at enhanced tumor selectivity and biocompatibility, which included application of a third-generation photosensitizing agent, i.e. xanthene-origin Rose Bengal (RB) co-encapsulated with up-converting NaYF4 nanoparticles (NPs) co-doped with lanthanide ions: Er3+ (2%) and Yb3+ (20%). The hybrid fluorophores were applied as components of double core nanocarriers (NCs) obtained by double (multiple) emulsion solvent evaporation process. Next, to improve the biocompatibility and photodynamic activity, biodegradable polymer: poly(lactide-co-glycolide) - PLGA and non-ionic surfactants with different hydrophobicity: Span 80 and Cremophor A25, were used. After the engineering process, controlled by dynamic light scattering (DLS) measurements, ζ-potential evaluation, transmission electron and atomic force microscopy (TEM and AFM) imaging, as well as optical analysis provided by measurements of the up-conversion emission spectra and luminescence kinetics for encapsulated only NaYF4:Er3+,Yb3+ NPs and co-encapsulated RB + NaYF4:Er3+,Yb3+ molecules, spherical polyester NCs with average size <200 nm, were tested on human melanoma (Me-45 and MeWo) cells and a control human keratinocyte (HaCaT) cell line. The photodynamic action of the investigated NCs was assessed by oxidoreductive potential measurements with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, that corresponds to percentage of the viable cells. Immunofluorescence and the NCs internalization studies were visualized by confocal laser scanning microscopy (CLSM studies). Our results indicated effective photosensitizer delivery into the cancer cells and significant photodynamic efficiency enhanced by the near infrared (NIR)-activation of the encapsulated hybrid cargo in the skin melanoma cells.

Experience with generic pegylated L-asparaginase in children with acute lymphoblastic leukemia and monitoring of serum asparaginase activity.

BACKGROUND: Pegylated asparaginase (P-Asp) though integral to acute lymphoblastic leukemia (ALL) therapy is often not accessible to patients in developing countries. We share our clinical experience with generic P-Asp along with monitoring of asparaginase activity. METHODS: In this prospective observational study, patients ≤18 years of age with ALL were assigned to receive either generic P-Asp or native asparaginase (N-Asp) in a non-randomized manner. Treatment protocol was based on ALL BFM-95 backbone. The dose of P-Asp was 1500 IU/m2 by intravenous route during induction (Ia) and re-induction (IIa) phase of therapy. RESULTS: N-Asp or P-Asp was administered to 52 and 54 of the 106 eligible patients respectively. Demographic and disease characteristics were comparable in both arms. The mean trough levels for N-Asp and P-Asp were 156.87 ± 22.35 IU/L and 216.03 ± 73.40 IU/L, respectively (p value <0.001) and all patients achieved therapeutic levels during Ia. Incidence of asparaginase-attributable toxicity was similar in the two arms in both phases of treatment, although hospitalization due to noninfectious causes was more common in P-Asp arm during Ia (13% versus 0%, p value, 0.01). Clinical hypersensitivity and silent inactivation were not observed during Ia while these occurred in 13% and 5% of patients in the N-Asp arm and P-Asp arms of IIa, respectively. The 2-year event free survival for P-Asp and N-Asp groups was 84% and 80.7%, respectively (p value 0.85). CONCLUSION: Generic P-Asp was observed to be efficacious and well tolerated in our patients and adequate therapeutic levels were sustained for 2 weeks.

Scientific and Regulatory Policy Committee Points to Consider: Histopathologic Evaluation in Safety Assessment Studies for PEGylated Pharmaceutical Products.

Colorless, intracytoplasmic vacuoles occur in multiple tissues in animals following repeated administration of polyethylene glycol (PEG)-conjugated molecules. The extent of vacuolation depends on physical characteristics and molecular backbone of the PEG and the dose, product, drug target/pharmacology, and duration of exposure. The collective experience gathered from multiple nonclinical toxicology studies of PEGylated biopharmaceuticals indicates that in general, PEG-related vacuolation is not associated with demonstrable cell and tissue damage or dysfunction and is reversible with sufficient duration of drug-free periods. Existing data are insufficient to predict whether nonclinical animal species differ in their sensitivity to develop PEG-associated vacuoles; however, recent data suggest that there may be species differences. Recent comprehensive reviews have addressed the basic challenges in developing PEGylated pharmaceutical products, including general reference to and description of PEG-associated tissue findings. These manuscripts have identified gaps in our current understanding of PEG-associated vacuolation, including the lack of a widely accepted standardized histological terminology and criteria to record and grade the severity of vacuolation as well as insufficient knowledge regarding the nature of the contents of these vacuoles. The goal of this article is to help address some of the gaps identified above by providing points to consider, including a pictorial review of PEG-associated microscopic findings, when evaluating and reporting the extent, severity, and significance (adversity or lack of adversity) of PEG-associated cytoplasmic vacuolation in safety assessment studies. [Box: see text].

BAY 94-9027, a PEGylated recombinant factor VIII, exhibits a prolonged half-life and higher area under the curve in patients with severe haemophilia A: Comprehensive pharmacokinetic assessment from clinical studies.

INTRODUCTION: Recombinant factor VIII (rFVIII) products with extended half-lives, such as BAY 94-9027, can potentially maintain higher FVIII levels for longer periods of time, thus providing improved bleeding protection vs standard-acting FVIII products. AIM: To characterize the pharmacokinetic (PK) profile of BAY 94-9027 from phase 1, phase 2/3 (PROTECT VIII) and phase 3 (PROTECT VIII Kids) clinical trials in adults, adolescents and children with severe haemophilia A METHODS: Patients with severe haemophilia A (FVIII <1%) with >50 FVIII exposure days (EDs) and no history of inhibitors were included in the phase 1 (18-65 years, ≥150 EDs), PROTECT VIII (12-65 years, ≥150 EDs) and PROTECT VIII Kids (<12 years, >50 EDs) trials. PK parameters were assessed following a 25-IU/kg or 60-IU/kg BAY 94-9027 dose in the phase 1 study after the first and repeated infusion, in PROTECT VIII after the first and repeated 60-IU/kg infusion and in PROTECT VIII Kids after a single 60-IU/kg infusion. The chromogenic assay was used to assess FVIII activity. RESULTS: Compared with sucrose-formulated rFVIII, BAY 94-9027 had reduced clearance that resulted in a ~1.4-fold increase in half-life and dose-normalized area under the curve (AUC). The BAY 94-9027 PK profile was comparable after single- and repeated-dose administrations. Dose-proportional increases were observed between 25- and 60-IU/kg administrations. BAY 94-9027 PK characteristics were age dependent, consistent with other FVIII products. CONCLUSIONS: BAY 94-9027 shows an extended half-life and increased AUC vs standard-acting FVIII products. These PK characteristics will result in higher FVIII levels for longer duration.

Investigation of the Discriminatory Ability of Pharmacokinetic Metrics for the Bioequivalence Assessment of PEGylated Liposomal Doxorubicin.

PURPOSE: The purpose of the study was to construct a population pharmacokinetic model for pegylated liposomal doxorubicin and use the final model to investigate the discrimination performance of pharmacokinetic metrics (e.g., Cmax, AUC and partial AUC) of various analytes (e.g., liposome encapsulated doxorubicin, free doxorubicin and total doxorubicin) for the identification of formulation differences by means of Monte Carlo simulations. METHODS: A model was simultaneously built to characterize the concentration time profiles of liposome-encapsulated doxorubicin and free doxorubicin using NONMEM. The different scenarios associated with changes in release rate (Rel) were simulated based on the final parameters. 500 simulated virtual bioequivalence (BE) studies were performed for each scenario, and power curves for the probability of declaring BE were also computed. RESULTS: The concentration time profiles of liposome-encapsulated doxorubicin and free doxorubicin were well described by a one- and two-compartment model, respectively. pAUC0-24 h and pAUC0-48 h of free doxorubicin was most responsive to changes in the Rel when the Rel (test)/Rel (reference) ratios decreased. In contrast, when the Rel (test) increased, AUC0-t of liposome-encapsulated doxorubicin was the most responsive metric. CONCLUSIONS: In addition to the traditional metrics, partial AUC should be included for the BE assessment of pegylated liposomal doxorubicin.

Efficacy assessment of self-assembled PLGA-PEG-PLGA nanoparticles: Correlation of nano-bio interface interactions, biodistribution, internalization and gene expression studies.

The aim of our study was to develop and compare the biological performance of two types of biodegradable SN-38 loaded nanoparticles (NPs) with various surface properties, composed of low and high Mw triblock PLGA-PEG-PLGA copolymers, applying rational quality and safety by design approach. Therefore, along with the optimization of crucial physico-chemical properties and in order to evaluate the therapeutical potential and biocompatibility of prepared polymeric nanoparticles, analysis of nano-bio interactions, cell internalization, gene expression and biodistribution studies were performed. The optimized formulations, one of low Mw and one composed of high Mw PLGA-PEG-PLGA copolymer, exhibited different characteristics in terms of surface properties, particle size, zeta potential, drug loading, protein adsorption and biodistribution, which may be attributed to the variations in nano-bio interface interactions due to different NP building blocks length and Mw. On the contrary to protein adsorption and biodistribution studies, both types of NPs exhibited similar results during cell internalization and gene expression studies performed in cell culture medium containing serum proteins. This pool of useful data for internalization and efficacy as well as the notable advance in the circulation time of low Mw NPs may be further employed for shaping the potential of the designed nanocarriers.

Enhanced oral delivery of risperidone through a novel self-nanoemulsifying powder (SNEP) formulations: in-vitro and ex-vivo assessment.

CONTEXT: The oral delivery of risperidone encounters a number of problems, such as pH dependent solubility and low bioavailability, due to its lipophilicity and aqueous insolubility. OBJECTIVE: To improve the solubility, dissolution and intestinal permeation thereby bioavailability of risperidone through a novel self-nanoemulsifying powder (SNEP) formulations. MATERIALS AND METHODS: Oleic acid, Tween® 20, PEG 600 and Aerosil® 200 were chosen as oil, surfactant, co-surfactant and carrier, respectively from solubility and emulsification studies. Ternary phase diagram was constructed to determine emulsifying region. RESULTS AND DISCUSSION: The Z-average and polydispersity Index of developed formulation was 83.1 nm and 0.306, respectively. Ex vivo permeation studies on isolated rat intestine indicated that the amount of risperidone permeated from SNEP formulation was increased around 4- and 1.8-fold than that of pure drug and marketed formulation, respectively. CONCLUSION: This developed SNEP formulations can be regarded as novel and commercially feasible alternative to the current risperidone formulations.

Safety Assessment of Alkyl PEG/PPG Ethers as Used in Cosmetics.

The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 131 alkyl polyethylene glycol (PEG)/polypropylene glycol ethers as used in cosmetics, concluding that these ingredients are safe in the present practices of use and concentration described in this safety assessment when formulated to be nonirritating. Most of the alkyl PEG/PPG ethers included in this review are reported to function in cosmetics as surfactants, skin-conditioning agents, and/or emulsifying agents. The alkyl PEG/PPG ethers share very similar physiochemical properties as the alkyl PEG ethers, which were reviewed previously by the CIR Expert Panel and found safe when formulated to be nonirritating. The alkyl PEG ethers differ by the inclusion of PPG repeat units, which are used to fine-tune the surfactant properties of this group. The Panel relied heavily on data on analogous ingredients, extracted from the alkyl PEG ethers and PPG reports, when making its determination of safety.

A 9-Month Toxicity and Toxicokinetic Assessment of Subcutaneous Pegylated Human C-peptide (CBX129801) in Cynomolgus Monkeys.

C-peptide is formed in the biosynthesis of insulin and is therefore deficient in patients with type 1 diabetes mellitus. A pegylated form of human synthetic C-peptide (CBX129801) has been developed to extend the half-life of the native peptide and is undergoing clinical investigation as replacement therapy to treat diabetic peripheral neuropathy. This monkey study was conducted to evaluate the toxicity of CBX129801 with weekly subcutaneous dosing for 39 weeks at dose levels of 0 (vehicle), 0.4, 1.33, and 4.0 mg/kg/wk. No systemic adverse effects were observed at any dose with maximal CBX129801 plasma concentrations of 735 to 1050 nmol/L during the dosing period (physiological range is 1-3 nmol/L). CBX129801-related effects were limited to minimal macrophagic vacuolization at the injection sites and in the associated draining (axillary) lymph nodes; these local effects largely resolved by the end of a 7-week recovery period. No systemic macrophagic vacuolization was observed. Additionally, there was no histological evidence for plaque formation in the major arteries of these nondiabetic animals.

Induction dosing of peginterferon alfa-2a (40 KD) and/or high-dose ribavirin in genotype 1 CHC patients with difficult-to-treat characteristics: pharmacokinetic and viral kinetic (PK/VK) assessment from PROGRESS.

BACKGROUND/AIMS: PROGRESS randomized chronic hepatitis C genotype 1 patients with a baseline viral load ≥400,000 IU/mL weighing ≥85 kg to regimens of 180 µg/week for 48 weeks or 360 µg/week for 12 weeks followed by 180 µg/week for 36 weeks peginterferon alfa-2a plus ribavirin. This analysis explored pharmacokinetics and early viral kinetics (VK) and evaluates differences between groups. METHODOLOGY: Blood samples for pharmacokinetic and VK analyses were collected from 51 patients enrolled in the PROGRESS study. RESULTS: Mean peginterferon alfa-2a trough concentration at week 12 was 11.7±4.3 ng/mL for 180 µg and 23.4±11.3 ng/mL for 360 µg. Early VK profiles suggested a trend towards an enhanced viral decline in the 360 µg groups with a mean decrease in HCV RNA at 48 hours post first dose of 1.04 log10 (IU/mL) compared with 0.76 log10 (IU/mL) in the 180 µg groups. Mean beta slope increased with dose, ranging from 0.38±0.26 log10 IU/week at 180 µg to 0.52±0.32 log10 IU/week at 360 µg. CONCLUSIONS: Early viral de clines may be enhanced with the 360 µg dose. These data may suggest the utility of high-dose peginterfer on alfa-2a plus direct-acting antivirals (DAA) in select difficult-to-treat populations.

Gold nanoparticles prepared by laser ablation in aqueous biocompatible solutions: assessment of safety and biological identity for nanomedicine applications.

Due to excellent biocompatibility, chemical stability, and promising optical properties, gold nanoparticles (Au-NPs) are the focus of research and applications in nanomedicine. Au-NPs prepared by laser ablation in aqueous biocompatible solutions present an essentially novel object that is unique in avoiding any residual toxic contaminant. This paper is conceived as the next step in development of laser-ablated Au-NPs for future in vivo applications. The aim of the study was to assess the safety, uptake, and biological behavior of laser-synthesized Au-NPs prepared in water or polymer solutions in human cell lines. Our results showed that laser ablation allows the obtaining of stable and monodisperse Au-NPs in water, polyethylene glycol, and dextran solutions. The three types of Au-NPs were internalized in human cell lines, as shown by transmission electron microscopy. Biocompatibility and safety of Au-NPs were demonstrated by analyzing cell survival and cell morphology. Furthermore, incubation of the three Au-NPs in serum-containing culture medium modified their physicochemical characteristics, such as the size and the charge. The composition of the protein corona adsorbed on Au-NPs was investigated by mass spectrometry. Regarding composition of complement C3 proteins and apolipoproteins, Au-NPs prepared in dextran solution appeared as a promising drug carrier. Altogether, our results revealed the safety of laser-ablated Au-NPs in human cell lines and support their use for theranostic applications.

An assessment of the pharmacokinetics, pharmacodynamics, and tolerability of GCPGC, a novel pegylated granulocyte colony-stimulating factor (G-CSF), in healthy subjects.

INTRODUCTION: A pegylated recombinant human granulocyte colony-stimulating factor (G-CSF) is effective in reducing the severity and duration of neutropenia. This study was performed to investigate the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of GCPGC, a new formulation of pegylated G-CSF, in healthy volunteers and to compare them with those of pegfilgrastim (Neulasta®). METHODS: Twenty-five healthy Korean male volunteers randomly received a single subcutaneous (SC) GCPGC injection at a dose of 30 (n = 10), 100 (n = 10), or 300 (n = 5) µg/kg or placebo in a 4:1 ratio in a double-blind manner. Additionally, 8 subjects received a SC dose of pegfilgrastim at 100 µg/kg. Blood samples were collected up to 14 days after both therapies. The absolute neutrophil count (ANC) and CD34(+) cell counts were the PD markers. RESULTS: After GCPGC administration, 4 different pharmacokinetic phases were identified, indicating target-mediated drug disposition (TMDD) for the elimination of GCPGC, which was slowed down as the dose was increased, resulting in a higher than proportional dose-normalized exposure to GCPGC. Although GCPGC was cleared faster than pegfilgrastim, leading to a 19 % lower systemic exposure to pegylated G-CSF, the increase in ANC and CD34(+) were ~20 % greater by GCPGC at 100 µg/kg than pegfilgrastim. Thrombocytopenia, splenomegaly, and hemoperitoneum occurred in one subject in the 300 µg/kg GCPGC group, which resolved completely with appropriate care. CONCLUSIONS: GCPGC showed a non-linear TMDD. The PK-PD characteristics of GCPGC at 30-100 µg/kg were comparable to those of pegfilgrastim at 100 µg/kg. GCPGC at 30-100 µg/kg was well tolerated in healthy Korean males.

Safety assessment of alkyl PEG ethers as used in cosmetics.

The CIR Expert Panel assessed the safety of Alkyl PEG Ethers as used in cosmetics. These ingredients primarily function in cosmetics as surfactants, and some have additional functions as skin-conditioning agents, fragrance ingredients, and emulsion stabilizers. The Panel reviewed available relevant animal and clinical data, as well as information from previous CIR reports; when data were not available for individual ingredients, the Panel extrapolated from the existing data to support safety. The Panel concluded that the Alkyl PEG ethers are safe as used when formulated to be nonirritating, and the same applies to future alkyl PEG ether cosmetic ingredients that vary from those ingredients recited herein only by the number of ethylene glycol repeat units.

Pegloticase: a novel agent for treatment-refractory gout.

OBJECTIVE: To evaluate efficacy and safety of pegloticase, approved by the Food and Drug Administration in September 2010 for treatment of patients with chronic treatment-refractory gout. DATA SOURCES: Literature searches were conducted using PubMed (1948-January 2012), TOXLINE, International Pharmaceutical Abstracts (1970-January 2012), and Google Scholar using the terms pegloticase, puricase, PEG-uricase, gout, uricase, and Krystexxa. Results were limited to English-language publications. References from selected articles were reviewed to identify additional citations. STUDY SELECTION AND DATA EXTRACTION: Studies evaluating the pharmacology, pharmacokinetics, safety, and efficacy of pegloticase for the treatment of chronic treatment-refractory gout were included. DATA SYNTHESIS: Pegloticase represents a novel intravenous treatment option for patients who have chronic gout refractory to other available treatments. Pegloticase is a recombinant uricase and achieves therapeutic effects by catalyzing oxidation of uric acid to allantoin, resulting in decreased uric acid concentrations. Results of published trials demonstrate the ability of pegloticase to maintain uric acid concentrations below 7 mg/dL in patients with chronic gout. Data supporting reduction of gout flares are limited. Pegloticase is well tolerated but associated with gout flares and infusion reactions. Other adverse events include nausea, dizziness, and back pain. During Phase 3 trials, 2 patients in the pegloticase biweekly group and 1 in the monthly group experienced heart failure exacerbation; another patient in the monthly group experienced a nonfatal myocardial infarction. Providers should exercise caution before administering pegloticase to patients with cardiovascular disease. The cost burden and safety profile may limit its use in practice, in addition to limited data available to support decreases in patient-centered outcomes (eg, gouty attacks). CONCLUSIONS: Pegloticase is an effective option for patients with symptomatic gout for whom current uric acid-lowering therapies are ineffective or contraindicated.

Comparison of fluence-to-dose conversion coefficients for deuterons, tritons and helions.

Secondary radiation in aircraft and spacecraft includes deuterons, tritons and helions. Two sets of fluence-to-effective dose conversion coefficients for isotropic exposure to these particles were compared: one used the particle and heavy ion transport code system (PHITS) radiation transport code coupled with the International Commission on Radiological Protection (ICRP) reference phantoms (PHITS-ICRP) and the other the Monte Carlo N-Particle eXtended (MCNPX) radiation transport code coupled with modified BodyBuilder™ phantoms (MCNPX-BB). Also, two sets of fluence-to-effective dose equivalent conversion coefficients calculated using the PHITS-ICRP combination were compared: one used quality factors based on linear energy transfer; the other used quality factors based on lineal energy (y). Finally, PHITS-ICRP effective dose coefficients were compared with PHITS-ICRP effective dose equivalent coefficients. The PHITS-ICRP and MCNPX-BB effective dose coefficients were similar, except at high energies, where MCNPX-BB coefficients were higher. For helions, at most energies effective dose coefficients were much greater than effective dose equivalent coefficients. For deuterons and tritons, coefficients were similar when their radiation weighting factor was set to 2.

Erythropoiesis-stimulating agents in renal medicine.

The four currently available erythropoiesis-stimulating agents (ESAs), the main drugs for correcting anemia in patients with chronic kidney disease (CKD), are epoetin alfa, epoetin beta, darbepoetin alfa, and continuous erythropoietin receptor activator. The last two have much longer half-lives, which means they can be administered less frequently. The expiry of the patents for epoetin alfa and epoetin beta some years ago opened up the way for the production of a number of biosimilars that are now marketed in the European Union. Because biosimilars cannot be identical to their originator, a complex and still-evolving regulatory policy has been generated, but there are still a number of issues concerning international naming, automatic substitution, and safety. All ESAs are effective in correcting renal anemia and increasing hemoglobin levels, but the choice of which to use should also take into account their pharmacokinetics and pharmacodynamics, their administration route, and economic issues. Following the publication of a number of trials indicating no benefit (and even possible harm) when ESAs are used to aim at near-normal hemoglobin levels in CKD patients, the hemoglobin target has become a major subject of discussion. According to the position statement of the Anemia Group of the European Renal Best Practice, it should generally be about 11-12 g/dL; however, a risk-benefit evaluation is warranted in individual patients, and high ESA doses driven by hyporesponsiveness should be avoided.