The pharmacokinetic profile, tolerability and safety of the iodinated, non-ionic, dimeric contrast medium Iosimenol 340 injection in healthy human subjects.

BACKGROUND: Iosimenol 340 injection is a new isotonic iodinated contrast medium for X-ray angiography. PURPOSE: To investigate the pharmacokinetics and biotransformation, tolerability, and safety of Iosimenol 340 in healthy human subjects. MATERIAL AND METHODS: Twenty-four subjects were enrolled and randomized to receive either Iosimenol 340 (0.5, 1.5 or 3.0 mL/kg) or placebo (0.9% saline). In each dosing group, six subjects received Iosimenol 340 and two subjects received placebo. Safety was assessed by physical examination, vital signs, electrocardiography, and laboratory tests. Adverse events were recorded throughout the study up to 14 days after dosing. Blood samples were collected from 10 min before until 48 h after the start of dosing and urine samples were collected from 15 min before until 96 h after the start of dosing. Iosimenol was quantified in plasma and urine by measuring iodine concentrations with X-ray fluorescence. High-performance liquid chromatography was used to assess iosimenol biotransformation. RESULTS: Mean half-lives (mean ± standard deviation [SD]) of iosimenol were 0.17 ± 0.08 h (10.2 ± 4.8 min) and 2.01 ± 0.32 h for distribution and terminal elimination phases, respectively. The apparent volume of distribution was 0.27 ± 0.05 L/kg, indicating distribution to the extracellular fluid volume. Iosimenol was excreted within 24 h without any sign of metabolic transformation. Thirty-two adverse events were observed in 14 subjects. All were mild or moderate, and were transient in nature. CONCLUSION: Iosimenol was not metabolized, had a distribution volume corresponding to the extracellular space, and was rapidly excreted through the kidneys by glomerular filtration. The area under the plasma concentration curve and the peak plasma concentration was proportional to dose, while clearance was independent of dose. Iosimenol 340 was well tolerated.

Intra-arterial and intravenous applications of Iosimenol 340 injection, a new non-ionic, dimeric, iso-osmolar radiographic contrast medium: phase 2 experience.

BACKGROUND: Iosimenol 340 injection is a new, dimeric, iso-osmolar, iodinated contrast medium for X-ray angiography. PURPOSE: To compare the safety and efficacy of iosimenol injection to iodixanol injection in two randomized, controlled phase 2 trials. MATERIAL AND METHODS: One hundred and forty-four adult patients were enrolled in the two trials, one for evaluation during arteriography and the other for evaluation during computed tomography. Safety was compared by assessing adverse events, vital signs, ECGs, and laboratory parameters. Efficacy was assessed as X-ray attenuation in the computed tomography (CT) trial and as the quality of contrast enhancement in the arteriography trial. RESULTS: There were no statistically significant differences in terms of safety or efficacy between the two contrast media. Both were well tolerated upon intravenous as well as intra-arterial injection. The most common adverse event was a feeling of warmth (observed in 35.1% of the patients with Iosimenol injection and 44.3% with iodixanol injection). CONCLUSION: Iosimenol upon intravenous as well as upon intra-arterial injection exhibits a safety profile and shows an efficacy similar to that of iodixanol.

First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis.

In chronic kidney disease both renal insufficiency and chronic inflammation trigger elevated hepcidin levels, which impairs iron uptake, availability. and erythropoiesis. Here we report the two first-in-human phase 1 trials of PRS-080#22, a novel, rationally engineered Anticalin protein that targets and antagonizes hepcidin. A single intravenous infusion of placebo or PRS-080#22 was administered to 48 healthy volunteers (phase 1a) and 24 patients with end stage chronic kidney disease (CKD) on hemodialysis (phase 1b) at different doses (0.08-16mg/kg for the phase 1a study and 2-8mg/kg for the phase 1b study) in successive dosing cohorts. The primary endpoint for both randomized, double-blind, phase 1 trials was safety and tolerability. Following treatment, all subjects were evaluable, with none experiencing dose limiting toxicities. Most adverse events were mild. One serious adverse event occurred in the phase 1b (CKD patient) study. There were no clinically significant changes in safety laboratory values or vital signs. PRS-080#22 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately three days in healthy volunteers and 10 to 12 days in CKD patients. Serum hepcidin levels were suppressed in a dose dependent manner and remained low for up to 48 hours after dosing. PRS-080#22 dose-dependently mobilized serum iron with increases in both serum iron concentration and transferrin saturation. No consistent changes were observed with regard to ferritin, reticulocytes, hemoglobin, and reticulocyte hemoglobin. Low titer anti-drug-antibodies were detected in five healthy volunteers but in none of the CKD patients. PRS-080#22, a novel Anticalin protein with picomolar affinity for hepcidin, was safe and well-tolerated when administered to healthy volunteers and CKD patients at all doses tested. The drug exhibited linear pharmacokinetics, longer half-life in CKD patients in comparison to healthy volunteers as well as expected pharmacodynamic effects which hold promise for further clinical studies.

MRI characteristics in focal hepatic disease before and after administration of MnDPDP: discriminant analysis as a diagnostic tool.

The aim of this study was to determine if different types of focal hepatic lesions can be differentiated by specific quantitative and qualitative imaging characteristics pre- and post-Mangafodipir trisodium (MnDPDP) administration using a computerized multivariable, discriminant analysis (DA). In a multicenter trial, 151 patients with focal liver disease were studied at 1.5 and 1.0 T using gradient-recalled echo T1 and fast spin-echo T2-weighted images pre and post MnDPDP (0.005 mmol/kg b.w.) i.v. administration. Analysis could be performed in 141 of 151 of the patients. The variables used in both single variable analysis and DA included contrast-to-noise ratios pre and post MnDPDP, presence of rim enhancement, margin, and heterogeneity of a lesion pre and post MnDPDP. The classification of diagnoses using DA was compared with a standard of reference (HCC in 23%, metastases in 25%, cyst in 13%, FNH in 10%, hemangioma in 11%, and other or no lesion in 18% of the patients; histology in 49%, long-term follow-up in 51% of the cases). In the differentiation of the various hepatic lesions, CNR together with the presence of heterogeneity or rim enhancement as variables for DA gave the highest sensitivity, specificity, and accuracy which ranged between 65 and 93, 44 and 83, and 65 and 86%, respectively. The DA models based on post-MnDPDP variables showed better classification results than the models based on pre-MnDPDP variables. An improvement of accuracy was observed when differentiating HCC from FNH lesion groups (48.9-67.4%; p < or = 0.05), and when differentiating HCC from metastasis lesion groups (68.3-84.1%; p < or = 0.01). In all regards there was no difference for T2-weighted images pre and post MnDPDP. By combining quantitative and qualitative variables, DA proved to be a useful tool in lesion discrimination. Due to considerable heterogeneity within some of the lesion type groups, the definite diagnostic impact of MnDPDP cannot be completely established yet, and further investigation is still necessary.