Fe(deferasirox)2: An Iron(III)-Based Magnetic Resonance Imaging T1 Contrast Agent Endowed with Remarkable Molecular and Functional Characteristics.

The search for alternatives to Gd-containing magnetic resonance imaging (MRI) contrast agents addresses the field of Fe(III)-bearing species with the expectation that the use of an essential metal ion may avoid the issues raised by the exogenous Gd. Attention is currently devoted to highly stable Fe(III) complexes with hexacoordinating ligands, although they may lack any coordinated water molecule. We found that the hexacoordinated Fe(III) complex with two units of deferasirox, a largely used iron sequestering agent, owns properties that can make it a viable alternative to Gd-based agents. Fe(deferasirox)2 displays an outstanding thermodynamic stability, a high binding affinity to human serum albumin (three molecules of complex are simultaneously bound to the protein), and a good relaxivity that increases in the range 20-80 MHz. The relaxation enhancement is due to second sphere water molecules likely forming H-bonds with the coordinating phenoxide oxygens. A further enhancement was observed upon the formation of the supramolecular adduct with albumin. The binding sites of Fe(deferasirox)2 on albumin were characterized by relaxometric competitive assays. Preliminary in vivo imaging studies on a tumor-bearing mouse model indicate that, on a 3 T MRI scanner, the contrast ability of Fe(deferasirox)2 is comparable to the one shown by the commercial Gd(DTPA) agent. ICP-MS analyses on blood samples withdrawn from healthy mice administered with a dose of 0.1 mmol/kg of Fe(deferasirox)2 showed that the complex is completely removed in 24 h.

Pharmacological and clinical evaluation of deferasirox formulations for treatment tailoring.

Deferasirox (DFX) is the newest among three different chelators available to treat iron overload in iron-loading anaemias, firstly released as Dispersible Tablets (DT) and more recently replaced by Film-Coated Tablets (FCT). In this retrospective observational study, pharmacokinetics, pharmacodynamics, and safety features of DFX treatment were analyzed in 74 patients that took both formulations subsequently under clinical practice conditions. Bioavailability of DFX FCT compared to DT resulted higher than expected [Cmax: 99.5 (FCT) and 69.7 (DT) µMol/L; AUC: 1278 (FCT) and 846 (DT), P < 0.0001]. DFX FCT was also superior in scalability among doses. After one year of treatment for each formulation, no differences were observed between the treatments in the overall iron overload levels; however, DFX FCT but not DT showed a significant dose-response correlation [Spearman r (dose-serum ferritin variation): - 0.54, P < 0.0001]. Despite being administered at different dosages, the long-term safety profile was not different between formulations: a significant increase in renal impairment risk was observed for both treatments and it was reversible under strict monitoring (P < 0.002). Altogether, these data constitute a comprehensive comparison of DFX formulations in thalassaemia and other iron-loading anaemias, confirming the effectiveness and safety characteristics of DFX and its applicability for treatment tailoring.

Safety and efficacy of deferasirox in patients with transfusion-dependent thalassemia: A 4-year single-center experience.

This study was organized to determine the efficacy and safety of deferasirox (DFX) in reducing the SF of patients with transfusion-dependent thalassemia (TDT). This is a retrospective, descriptive study of 101 transfusion- dependent patients with thalassemia major who were followed for 48 months. Twenty-nine patients who used an alternative chelator either alone or combined, who were not compliant to the treatment, changed the drug due to adverse reactions, and had multiple transfusions and did not complete 4 years of DFX use were excluded. A total 72 out of 101 patients completed the study. SF decreases were noted for the 6-12 and >18-year age groups, from a median of 1532 ng/mL to 1190 ng/mL, and from 1386 ng/mL to 1165 ng/mL, respectively (p > 0.05). The proportion of patients with SF concentrations >2000 ng/mL is decreased (29% at baseline decreased to 15% at the end of the study) during the 48 months. The median SF of those who used <30 mg/kg/day (n = 38) increased from 767 ng/mL to 1006 ng/mL, whereas the >30 mg/kg/day (n = 34) group's SF concentrations decreased from a median of 1575 ng/mL to 1209 ng/mL (p = 0.029). The decrease of median SF values for Syrian patients was statistically significant (p = 0.043). Most common adverse events were gastric irritation symptoms (19.4%). The total DFX discontinuation ratio was calculated as 9.7%. Although dosages between 25-30 mg/kg/day are adequate to stabilize SF concentrations higher dosages are needed to achieve a statistically significant decrease.

Effect of Genetic Polymorphisms on the Pharmacokinetics of Deferasirox in Healthy Chinese Subjects and an Artificial Neural Networks Model for Pharmacokinetic Prediction.

BACKGROUND AND OBJECTIVE: Deferasirox is an oral iron chelator used to reduce iron levels in iron-overloaded patients with transfusion-dependent anemia or non-transfusion-dependent thalassemia. This study investigated the effects of genetic polymorphisms on the pharmacokinetics of deferasirox in healthy Chinese subjects and constructed a pharmacokinetic prediction model based on physiologic factors and genetic polymorphism data. METHODS: Twenty-eight subjects were enrolled in a randomized, open-label, two-period crossover study, and they received a single dose of one of two formulations of deferasirox (20 mg/kg) with a 7-day washout interval between the two periods. The plasma defersirox concentration was determined using a validated liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters were calculated using the noncompartmental method. The polymorphisms of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), UGT1A3, multidrug resistance protein 2 (MRP2), cytochrome P450 1A1 (CYP1A1), and breast cancer resistance protein 1 (BCRP1) were genotyped using Sanger sequencing. A back-propagation artificial neural network (BP-ANN) model was used to predict the pharmacokinetics. RESULTS: The UGT1A1 rs887829 C > T single-nucleotide polymorphism (SNP) significantly influenced the area under the plasma concentration-time curve and the terminal half-life. Neither the MRP2 rs2273697 G > A SNP nor BCRP1 rs2231142 G > T SNP altered the absorption, disposition, and excretion of the drug. The BP-ANN model had a high goodness-of-fit index and good coherence between the predicted and measured concentrations (R2 = 0.921). CONCLUSION: Metabolic enzyme-related genetic polymorphisms were more strongly associated with the pharmacokinetics of deferasirox than membrane transporter-related genetic polymorphisms in the Chinese population. TRIAL REGISTRATION: www.Chinadrugtrials.org.cn CTR20191164.

Solid Dispersion Pellets: An Efficient Pharmaceutical Approach to Enrich the Solubility and Dissolution Rate of Deferasirox.

Deferasirox (DFX) is an oral iron-chelating agent and classified into class II of the Biopharmaceutics Classification System. Low bioavailability of the drug due to insufficient solubility in physiological fluids is the main drawback of DFX. The idea of the current study was to explore the potential of solid dispersion (SD) as an effective method to improve the dissolution rate of DFX in pellets. The SDs were made by the solvent evaporation technique using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K25 with different drug-to-carrier ratios. Then, the dispersion was milled and mixed with other components and the mixture layered on sugar-based cores by pan coating technique. The pellets were evaluated in terms of size distribution, morphology (SEM), and dissolution behaviour. Drug-polymer interactions were studied using differential scanning calorimetry (DSC), X-ray diffraction study (XRD), and Fourier transformation infrared (FTIR) spectroscopy. The pellets coated with SD showed a remarkable rise in the solubility of DFX than that of free drug-loaded pellets. The dispersion with PVP K25 showed a faster dissolution rate as compared to other mixtures. The DSC and XRD analysis indicated that the drug was in the amorphous state when dispersed in the polymer. The FTIR studies demonstrated any ruled out interaction between drug and polymer. The SEM showed smoothness on the surface of the pellets. It is resolved that the SD method considerably enriched the dissolution rate of DFX in pellets, which can also be utilized for other poorly water-soluble drugs.

ABCC2 c.-24 C>T single-nucleotide polymorphism was associated with the pharmacokinetic variability of deferasirox in Chinese subjects.

PURPOSE: Our aim was to evaluate the influence of genetic polymorphisms involved in the metabolism and transportation of deferasirox on deferasirox pharmacokinetics in the Chinese population. METHODS: Thirty-eight healthy Chinese subjects were administered with a single dose of 20 mg kg-1 deferasirox. Allelic discriminations for eight single-nucleotide polymorphisms (SNPs) in UDP-glucuronosyltransferase 1A1, 1A3 (UGT1A1, UGT1A3), multidrug resistance protein 2 (MRP2, ABCC2), and breast cancer resistance protein (BCRP, ABCG2) were performed. The concentrations of deferasirox in the plasma were determined by UPLC-MS/MS. RESULTS: Subjects carrying ABCC2 c.-24 T allele had a 65% higher clearance (CL/F) and 42% lower area under the concentration-time curve from 0 to 72 h (AUC0-72h) as compared with non-carriers (P = 0.008, P = 0.011, respectively). ABCC2 c.-24 T was also associated with 59% shorter half-life (T1/2) and 17% shorter mean residence time (MRT) (P = 0.030, P = 0.014, respectively). ABCC2 1249A was associated with a marginal increase in deferasirox Cmax (P = 0.07). Genetic polymorphisms of UGT1A1, UGT1A3, and ABCG2 did not significantly influence the pharmacokinetics of deferasirox. Subjects with UGT1A1 211GG-(-1352)CC-(-3156)GG haplotype had higher AUC0-72h than others. Since only two subjects were recruited in the GG-CC-GG group, further confirmative studies were warranted. CONCLUSIONS: ABCC2 c.-24 C>T was associated with the pharmacokinetic variability of deferasirox in Chinese subjects. This study revealed an important role of MRP2 in the pharmacokinetics of deferasirox and drew attention to drug combination with MRP2 inhibitors like cyclosporine and methotrexate in deferasirox therapy.

Clinical relevance of deferasirox trough levels in ß-thalassemia patients.

We evaluated the role of deferasirox therapeutic drug monitoring in order to avoid toxicity or treatment failure. Plasma concentrations, measured between two consecutive liver iron determinations, were determined at the end of dosing interval. Fifty-four ß-thalassemic adult patients were enrolled: 50% were males; median age was 32.3 years (IQR 19.1-41.7 years) and median body mass index was 22.25 kg/m2 (IQR 20.24-23.75 kg/m2 ). The mean deferasirox dose was 28.6 ± 6.3 mg/kg/d and mean plasma concentration was 17.3 ± 16.8 µg/mL. Drug levels showed lower results in males. Deferasirox concentration was significantly correlated with serum creatinine levels (P = .01) and serum ferritin (P < .0001). The assessment of deferasirox therapeutic drug monitoring could help clinicians to predict patient responses and to optimize the therapy.