TESLASCAN Injection (mangafodipir trisodium) is a complex formed between a chelating agent (fodipir) and a paramagnetic metal ion, manganese. Mangafodipir shortens the spin lattice (longitudinal) relaxation time (T₁) of targeted tissues during MRI, leading to an increase in signal intensity (brightness) of the tissues.

Mangafodipir has two components: fodipir and a manganese (II) ion.Each has different pharmacokinetics, metabolism, and modes of elimination. After intravenous administration of TESLASCAN, the pharmacokinetics of each component were investigated.

Fodipir: When TESLASCANis labeled with the ¹⁴C-label residing in the fodipir, after a single intravenous dose of 5 µmol/kg of ¹⁴C-TESLASCAN in 6 healthy volunteer men, the mean ± SD area under the radioactivity plasma concentration curve (AUC) is 22.7 ± 3.2 µg*h/mL.

Manganese (II) ion: Generally, the total body store of manganese in adults is 20 mg. Most of this is from dietary intake (2-5 mg/day).TESLASCAN Injection contains 2.75 mg/mL of chelated manganese. In a 70 kg adult, 5 µmol/kg of TESLASCAN Injection contains 19.2 mg of chelated manganese. Therefore, a single injection of TESLASCAN will approximately double the total body store of manganese before excretion occurs. In a study of 31 healthy volunteers (16 men and 15 women), after a single intravenous dose of 5 µmol/kg TESLASCAN, areas under the manganese serum concentration versus time curves (AUC) were 15.8 ± 5.8 µM*h (mean ± SD) and 16.0 ± 2.9 µM*h (mean ± SD), respectively.(See Elimination section for details on excretion.)

DISTRIBUTION

Mangafodipir itself does not bind to plasma proteins in vitro; however, manganese (II) and manganese (III) are known to bind to plasma proteins in vitro.

In pregnant rats who received ⁵⁴Mn, radioactivity was detected in the placenta and in the fetus.(See Pregnancy section.)

After intravenous injection, mangafodipir trisodium is metabolized by the removal of two phosphate groups and the exchange of the manganese ion for an endogenous zinc ion. This produces two major metabolites, manganese dipyridoxyl ethylenediamine diacetic acid (MnPLED) and zinc dipyridoxyl ethylenediamine diacetic acid (ZnPLED).

In plasma, the mangafodipir trisodium is not detected after 2 hours.The MnPLED concentration peaks within ten minutes and is not detected after 1 hour.The ZnPLED metabolite reaches maximum concentration 20 minutes after injection and then decreases slowly. By 24 hours the two major metabolites (MnPLED and ZnPLED) represent 12% and 57% of the administered dose, respectively.

Fodipir:When TESLASCAN is labeled with the ¹⁴C in the fodipir, after intravenous administration of 5 µmol/kg ¹⁴C-mangafodipir trisodium to 6 healthy volunteer men, approximately 92% of the radioactivity administered is eliminated in the urine over 24 hours. Negligible amounts (0.3%) are recovered in feces over 168 hours.The total plasma clearance of radioactivity was 11.6 ±2.1 L/h (0.15 ±0.02 L/h/kg mean ±SD). The apparent terminal half-life (mean ±SD) of elimination of radioactivity from plasma is 2.09 ± 0.47 hours.

Manganese (II) ion: After intravenous administration of TESLASCAN, the initially high serum manganese concentrations drop rapidly and approach detection limits (or baseline levels) within a few hours. Approximately 15% of the dose administered of the manganese (II) ion of mangafodipir is eliminated in the urine within the first 24 hours after injection and an additional 59% is excreted in the feces over the following 5 days.The remainder is eliminated in urine and feces gradually.

The dialyzability of TESLASCAN Injection and its metabolites has not been studied.

Hepatic Insufficiency: A single intravenous dose of 5 µmol/kg of TESLASCAN was administered to 31 subjects with normal hepatic function (16 men and 15 women) and 10 subjects with impaired hepatic function (5 men and 5 women).In the patients with impaired hepatic function (5 men and 5 women), after a single intravenous dose of 5 µmol/kg TESLASCAN, for manganese, AUCs were 23.3 ±4.3 µM*h (mean ±SD) and 24.6 ±4.0 µM*h (mean ±SD), respectively.(See Pharmacokinetics of Manganese Ion for comparative values in healthy volunteers.) Manganese (II) ion serum levels at 1 hour after injection were 10% or less of maximal values.

Manganese (II) ion half-life: In both healthy subjects and subjects with hepatic impairment, the immediate distribution half-life (determined over the interval from 5 minutes to 2 hours after injection) was 24.4 ± 7.7 min (mean ± SD). However, the terminal half-lives were longer, tH = 10.1 ± 20.3 hrs and tH = 26.7 ± 19.0 hrs, respectively, for healthy and hepatically impaired subjects.

Statistically significant differences were not detected in the elimination half-lives between men and women who were either healthy or had hepatic impairments, nor were there differences in the overall urinary or fecal recovery of manganese (II) ion in men and women who were either healthy or had hepatic impairments.(See Table 1 for details.)

Pharmacokinetic differences due to age in adults or in pediatric patients after intravenous TESLASCAN were not studied.

Pharmacokinetic differences due to race after intravenous TESLASCAN were not studied.

Drug interactions were not studied.

Pharmacokinetic studies with intravenous TESLASCAN were performed with nonfasted volunteers or patients.

Mangafodipir enhances T₁ signal intensity.In a study of 12 healthy volunteer men, mangafodipir began to increase the signal intensity of liver tissue within 1-3 minutes, and steady-state enhancement was reached in about 5-10 minutes. Liver enhancement after TESLASCAN Injection administration is detectable in patients up to 24 hours after injection. After mangafodipir trisodium administration, liver lesions may present in a number of different patterns of contrast enhancement.(See Clinical Trials section.)

TESLASCAN Injection was studied in four multicenter, randomized, blinded, controlled clinical trials in a total of 546 adults who underwent hepatic MRI for evaluation of known or suspected focal liver disease.

In two of these studies, 404 adults (244 men, 160 women; 79% Caucasian, 10% Black, 6% Asian, 5% other races;mean age 58;range, 19-86 yr) received TESLASCAN 5 µmol/kg.Of these, 369 patients had images that were evaluated for efficacy. All patients were imaged in three ways: 1) by contrast-enhanced computed tomography (CECT), 2) by unenhanced magnetic resonance imaging (MRI) and 3) by TESLASCAN Injection MRI.TESLASCAN Injection MRIs were obtained 15 minutes after injection (median, 20 minutes;range, 2-134 minutes).The sets of images were evaluated blindly as CECT alone, unenhanced MR images alone, TESLASCAN-enhanced MR images alone, and paired comparisons of the unenhanced and TESLASCAN-enhanced MRIs. Each liver lesion identified was rated for the presence of a specific cellular process (hepatocellular, nonhepatocellular, malignant, nonmalignant, or uncertain disease);a specific diagnosis (focal nodular hyperplasia, regenerative nodule, fatty infiltration, hepatoma/hepatocellular carcinoma, metastasis, cyst, adenoma, hemangioma or unknown); and the lesions pattern of enhancement (homogeneous, inhomogeneous, central, peripheral thin rim, peripheral thick rim, peripheral linear foci, peripheral nodular, or no enhancement). Histopathology was obtained for some lesions.An overall final diagnosis was based on clinical, histopathologic, and all imaging information except the TESLASCAN MRI. The analysis is based on the extent of agreement between the diagnosis from the TESLASCAN MRI versus the histopathologic diagnosis for each lesion, the correct number of lesions detected, and the diagnosis of each lesion or disease state.The results are reported as complete agreement (with all lesions and diagnoses) or essential agreement (with diagnoses but not necessarily all lesions).

Based upon these two studies, TESLASCAN Injection enhanced MRI contrast on the T₁-weighted pulse sequences.Table 2 shows the proportions of patients for whom the imaging diagnosis had complete or essential agreement with the final diagnosis. In both studies TESLASCAN MRI alone and the paired reading of TESLASCAN MRI each had a statistically significant higher extent of agreement with the final diagnosis than did unenhanced MRI.

In the above two studies, 105 individual lesions had histopathologic confirmation. Of these confirmed lesions, the proportion of correctly detected and correctly characterized lesions is shown in Table 3.

In two other studies of patients who received 5 µmol/kg of TESLASCAN, the efficacy of TESLASCAN Injection during delayed imaging was evaluated.In these two studies, 142 adult patients were given TESLASCAN(84 men, 58 women; 77% Caucasian, 15% Black, 4% Asian, 4% other races;mean age 58;range, 24-83 years). TESLASCAN-enhanced images for 140 patients were blindly evaluated for efficacy. TESLASCAN MRI imaging was performed at 15 minutes, 4 hours, and 24 hours after injection.The contrast enhancement results were comparable to those in the above studies and were similar at all time points.

In all four studies, each individual lesions pattern of enhancement was coded as homogeneous, inhomogeneous, central, peripheral thin rim, peripheral thick rim, peripheral linear foci, peripheral nodular, or no enhancement. For the majority of histopathologically confirmed lesions, the pattern of TESLASCAN enhancement correlated with the hepatocellular disorders (having homogeneous, inhomogeneous, or central enhancement) or with the nonhepatocellular disorders (having peripheral or no enhancement).In the 121 patients who had malignant disease, 58 (47.9%) did not enhance, 20 (16.5%) were inhomogeneous, 15 (12.4%) had a thin peripheral rim, 12 (9.9%) had a thick peripheral rim, 12 (9.9%) were homogeneous and 4 (3.3%) had a variety of other patterns.For the 24 patients with nonmalignant disease, 13 (54%) did not enhance, 8 (33.3%) had homogeneous patterns, and 3 (12%) had a variety of other patterns.Table 4 shows the patterns of enhancement that are seen in patients with histologically confirmed hepatocellular or nonhepatocellular disease.

Malignancy cannot be distinguished by the pattern of enhancement, or by the presence or absence of enhancement.

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