Dy-EOB-DTPA: tolerance and pharmacokinetics in healthy volunteers and preliminary liver imaging in patients

W Krause, M Mahler, B Hanke, W Milius, J Kaufmann, P Rogalla, B Hamm
Investigative Radiology 2001, 36 (8): 431-44

RATIONALE AND OBJECTIVES: To investigate the tolerance and pharmacokinetics of the new liver-specific x-ray contrast agent Dy-EOB-DTPA [(4S)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid, dysprosium (Dy) complex, disodium salt] in healthy volunteers and to obtain preliminary imaging data by abdominal spiral computed tomography (CT) in tumor patients with liver metastases.

METHODS: A total of 40 healthy male volunteers received 10-minute intravenous infusions of 0.05, 0.1, 0.25, 0.375, or 0.5 mmol/kg Dy-EOB-DTPA (n = 6 per dose group) or placebo (n = 10). Blood, urine, and feces were sampled for Dy measurements by inductively coupled plasma atomic emission spectrometry (ICP-AES) and for the detection of possible metabolites by high-performance liquid chromatography analysis with ICP-AES detection. Safety parameters were determined before, during, and after the study. Two patients with suspected liver metastases first received 120 mL of iopromide (300 mg iodine/mL; approximately 0.6 mmol/kg) and, 24 or 72 hours later, Dy-EOB-DTPA at a dose of 0.25 mmol/kg. Computed tomography images were obtained 50 seconds after iopromide administration and before and 90 minutes after Dy-EOB-DTPA administration.

RESULTS: Dysprosium-EOB-DTPA was well tolerated. At the higher doses (0.375 and 0.5 mmol/kg), there was a slight increase in side effect intensity. In general, nausea, headache, and paresthesia mainly were reported as mild to moderate adverse events. Laboratory parameters did not exceed the normal range. Electrocardiographic, vital sign, or hemodynamic parameters were not affected by contrast agent administration. The terminal half-life of elimination of Dy-EOB-DTPA was approximately 1.5 hours, total clearance was 2 to 3 mL x min(-1) x kg(-1), and the renal clearance was approximately 1.5 mL x min(-1) x kg(-1). There was a significant dose dependence for the following parameters: maximal concentration in blood, terminal half-life, mean residence time, total clearance, urinary excretion, and fecal excretion. The volume of distribution in the steady state and renal clearance were not dependent on dose. In the blood and urine, no metabolites of Dy-EOB-DTPA could be detected. In the tumor patients, CT scanning after Dy-EOB-DTPA injection increased the number of detected metastases from 27 (plain scan) to 40 (iopromide) and then to 41 (Dy-EOB-DTPA) in patient No. 1 and from 1 (plain scan and iopromide) to 3 (Dy-EOB-DTPA) in patient No. 2.

CONCLUSIONS: Dysprosium-EOB-DTPA was shown to be a well-tolerated liver-specific contrast agent. Its pharmacokinetic profile is characterized by a terminal half-life of approximately 1.5 hours. There are indications of saturation of liver uptake at the highest dose level of 0.5 mmol/kg. In comparison with plain scans and scans performed after iodinated contrast agent administration, Dy-EOB-DTPA seems to increase the number of detectable liver lesions.

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