Enhanced specificity due to method specific limits for relative ion intensities in a high-performance liquid chromatography - tandem mass spectrometry method for iohexol in human serum.

Background Accurate assessment of kidney function is needed for a variety of clinical indications and for research. The measurement of the serum clearance of iohexol has emerged as a feasible method to reach this objective. We report the analytical validation and clinical application of a new high-performance liquid chromatography (HPLC) - tandem mass spectrometry (MS/MS) assay to quantify iohexol in human serum. Specificity was enhanced due to the use of method specific acceptance limits for relative ion (RI) intensities. Methods The internal standard ioversol was added to 50 µL serum prior to protein precipitation with methanol. Linear gradient elution was performed on a Waters Oasis® HLB column. Three transitions for both iohexol and ioversol were monitored allowing calculation of RIs. Measurements acquired during method validation were used as a training set to establish stricter acceptance criteria for RIs which were then tested retrospectively on clinical routine measurements (86 measurements) and on mathematically simulated interferences. Results The method was linear between 5.0 µg/mL (lower limit of quantification [LLOQ]) and 100.3 µg/mL iohexol. Intraday and interday imprecision were ≤2.6% and ≤3.2%, respectively. Bias was -1.6% to 1.5%. All validation criteria were met, including selectivity, recovery, extraction efficiency and matrix effects. Retrospectively acceptance limits for RIs could be narrowed to ±4 relative standard deviations of the corresponding RIs in the training set. The new limits resulted in an enhanced sensitivity for the simulated interferences. Conclusions Criteria for validation were met and the assay is now used in our clinical routine diagnostics and in research.

Quality by Design approach in the development of hydrophilic interaction liquid chromatographic method for the analysis of iohexol and its impurities.

This study presents the development of hydrophilic interaction liquid chromatographic method for the analysis of iohexol, its endo-isomer and three impurities following Quality by Design (QbD) approach. The main objective of the method was to identify the conditions where adequate separation quality in minimal analysis duration could be achieved within a robust region that guarantees the stability of method performance. The relationship between critical process parameters (acetonitrile content in the mobile phase, pH of the water phase and ammonium acetate concentration in the water phase) and critical quality attributes is created applying design of experiments methodology. The defined mathematical models and Monte Carlo simulation are used to evaluate the risk of uncertainty in models prediction and incertitude in adjusting the process parameters and to identify the design space. The borders of the design space are experimentally verified and confirmed that the quality of the method is preserved in this region. Moreover, Plackett-Burman design is applied for experimental robustness testing and method is fully validated to verify the adequacy of selected optimal conditions: the analytical column ZIC HILIC (100 mm × 4.6 mm, 5 µm particle size); mobile phase consisted of acetonitrile-water phase (72 mM ammonium acetate, pH adjusted to 6.5 with glacial acetic acid) (86.7:13.3) v/v; column temperature 25 °C, mobile phase flow rate 1 mL min(-1), wavelength of detection 254 nm.

Safety and diagnostic image quality of iopromide: results of a large non-interventional observational study of European and Asian patients (IMAGE).

BACKGROUND: Iodine-based contrast agents such as iopromide play a central role in improving the diagnostic quality of imaging modalities using ionizing radiation. PURPOSE: To investigate the safety and diagnostic image quality of iopromide in the routine clinical setting. MATERIAL AND METHODS: This was an international, multicenter, prospective, single-arm, non-interventional study (NIS). The study was performed in out- and inpatients in 738 study centers in 21 countries in Europe and Asia. Iopromide was administered in a routine manner, in compliance with the local package insert. The use of premedication was at the discretion of the attending physician. Case report forms for 44,835 patients were analyzed (57.4% men). The median age of the patients was 55 years. RESULTS: For the vast majority of patients (94.8%), the contrast quality was rated as 'good' (55.8%) or 'excellent' (39.0%). For 1265 (2.8%) patients, there were reports of adverse drug reactions (ADRs) excluding tolerance indicators (TIs) (i.e. injection site warmth, feeling hot, or injection site pain of mild intensity). At least one ADR including TIs was reported in 2415 (5.4%) patients. There were 11 (0.02%) patients with serious ADRs, and no drug-related deaths. Events of injection site warmth and/or feeling hot were reported by 3.5%, nausea and/or vomiting by 0.96%, and urticaria, erythema, and/or rash by 0.54% of patients. Patients at risk for an acute idiosyncratic reaction (i.e. patients with a history of bronchial asthma, allergies, and/or contrast media reaction) had a higher incidence of ADRs compared with the overall study population. At-risk patients who did not receive premedication reported distinctly more ADRs compared with those who received premedication (12.0% versus 5.9%). CONCLUSION: Iopromide was shown to be a well-tolerated contrast agent whose usage resulted in high image quality. No unknown ADRs were observed. Premedication with antiallergy drugs should be considered in at-risk patients.

Renal safety in pediatric imaging: randomized, double-blind phase IV clinical trial of iobitridol 300 versus iodixanol 270 in multidetector CT.

BACKGROUND: It is debated whether iso-osmolar and low-osmolar contrast media are associated with different incidences of contrast medium-induced nephropathy (CIN) in patients with renal insufficiency. OBJECTIVE: To compare the incidence of CIN in children undergoing contrast-enhanced multidetector computer tomography (MDCT) with intravenous injection of low-osmolar (iobitridol, Xenetix® 300) or an iso-osmolar (iodixanol, Visipaque® 270) iodinated contrast medium. MATERIALS AND METHODS: One hundred forty-six children with normal renal function were included in this multicenter trial and underwent contrast-enhanced MDCT. The primary endpoint was the relative change in creatinine clearance from 48 h pre- to 72 h postcontrast medium administration using a noninferiority analysis in the intent-to-treat (ITT, n = 128) and per protocol (n = 68) populations. Secondary endpoints were incidence of CIN, global image quality, diagnostic efficacy and clinical safety. RESULTS: In the ITT population, the noninferiority of iobitridol over iodixanol was demonstrated. CIN incidence was 4.8% (three cases) with iobitridol and 10.6% (seven cases) with iodixanol (not significant). No statistically significant differences were observed for the secondary endpoints. CONCLUSION: Comparable satisfactory safety profiles were confirmed for both contrast media, with no significant difference in the incidence of CIN in children with normal renal function.

Myelography in the dog with non-ionic contrast media at different iodine concentrations.

Image quality and side effects were evaluated retrospectively in a series of 183 myelographic studies performed with two non-ionic contrast media (iohexol and iopamidol) at different concentrations. Side effects during and following the procedure were recorded. Image quality was assessed using an arbitrary scoring system and statistical analysis was performed with the cross-tabulation test (4 x 2 table) by comparing two groups receiving contrast medium at higher and lower concentrations. No significant differences in side effects were observed between the two groups but the ratings for image quality were significantly higher in the group receiving contrast medium at the higher concentration than in the group receiving the lower concentration. The results suggest that a high concentration of non-ionic contrast media can safely be used in dogs and may improve image quality.

Assessing the effectiveness of X-ray contrast media for abdominal computed tomographic examinations: comparison of four low-osmolality agents.

The objective of this investigation was to assess the effectiveness of four iodinated X-ray contrast media for abdominal computed tomographic (CT) examinations. Fifty-three patients were prospectively randomized to receive iohexol 300 mgI/ml (100 ml, n = 17), ioversol 320 mgI/ml (100 ml, n = 13), iopromide 300 mgI/ml (75 ml, n = 12), or iopentol 300 mgI/ml (100 ml, n = 11) to perform a dynamic contrast-enhanced abdominal CT. Image-enhancement profiles for the liver, aorta, and vena cava were studied. The maximum liver enhancement, the time to maximum liver enhancement, and the area under the hepatic enhancement-time curve (AUC) were determined for each examination. Liver-enhancement profile showed significant differences between the four contrast agents, with lower values for iopromide towards the final part of the CT examination (P < 0.05). Hepatic peak values were attained earlier for iopromide, although these were lower than those produced by any other of the agents evaluated in this study. Iopentol produced fast and intense hepatic peaks. Consequently, high AUC values were obtained with iopentol, low values were obtained with iopromide (P < 0.05), although this can be explained by the lower amount of contrast medium contained in the commercial vial and administered to the patient (75 ml vs 100 ml). When normalized to a 100 ml dose, the AUC value for iopromide becomes even higher than the average of the other three agents (P = 0.05). Ioversol, although available and administered as a more concentrated solution (320 mg/ml), was comparable to the less concentrated iohexol and iopentol (300 mgI/ml).(ABSTRACT TRUNCATED AT 250 WORDS)