Omniscan Pharmacology, Pharmacokinetics, Studies, Metabolism - Gadodiamide

Omniscan Pharmacology, Pharmacokinetics, Studies, Metabolism - Gadodiamide

CLINICAL PHARMACOLOGY

The pharmacokinetics of intravenously administered gadodiamide in normal subjects conforms to an open, two-compartment model with mean distribution and elimination half-lives (reported as mean ± SD) of 3.7 ± 2.7 minutes and 77.8 ± 16 minutes, respectively.

Gadodiamide is eliminated primarily in the urine with 95.4 ± 5.5% (mean ± SD) of the administered dose eliminated by 24 hours. The renal and plasma clearance rates of gadodiamide are nearly identical (1.7 and 1.8 mL/min/kg, respectively), and are similar to that of substances excreted primarily by glomerular filtration. The volume of distribution of gadodiamide (200 ± 61 mL/kg) is equivalent to that of extracellular water. Gadodiamide does not bind to human serum proteins in vitro.

In magnetic resonance imaging, visualization of normal and pathological brain and spinal tissue depends in part on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration of the spin-lattice or longitudinal relaxation time (T₁); and variation of the spin-spin or transverse relaxation time (T₂). OMNISCAN is a paramagnetic agent with unpaired electron spins which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent.

By increasing the relaxation rate, OMNISCAN decreases both the T₁ and T₂ relaxation times in tissues where it is distributed. At clinical doses, the effect is primarily on the T₁ relaxation time, and produces an increase in signal intensity. OMNISCAN does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier (e.g., cysts, mature postoperative scars, etc). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of OMNISCAN in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of OMNISCAN in various lesions are not known.

There is no detectable biotransformation or decomposition of gadodiamide.

Pharmacokinetic and pharmacodynamic studies have not been systematically conducted to determine the optimal dose and optimal imaging time in patients with abnormal renal function or renal failure, in the elderly, or in pediatric patients with immature renal function.

In early clinical trials of 439 adults, OMNISCAN 0.1 mmol/kg was evaluated and found to be useful in providing contrast enhancement in CNSMRI in adults. OMNISCANwas also evaluated in a trial in 57 adults (34 men, 23 women) who had an indication for CNS MRI. These patients had a mean age of 47 years (range 21 to 82 years). Of these, 93% were Caucasian, 2% Black, and 5% other races. All patients were studied with sequential dosing of OMNISCAN 0.1 mmol/kg followed by 0.2 mmol/kg within 20 minutes (for cumulative dose of 0.3 mmol/kg). The results of the noncontrast enhanced MRI, the OMNISCAN 0.1 mmol/kg enhanced, and the cumulative OMNISCAN 0.3 mmol/kg (0.1 followed by 0.2 mmol/kg)enhanced MRIs were compared blindly. In 54/56 (96%) of all patients, contrast enhancement was evident with both the 0.1 mmol/kg and cumulative 0.3 mmol/kg (0.1 mmol/kg followed by 0.2 mmol/kg) doses.

In comparison to the noncontrast MRI, increased numbers of brain and spine lesions were noted in approximately 42% of patients who received OMNISCAN at any dose. In comparisons of 0.1 mmol/kg versus 0.3 mmol/kg, the results were comparable in 25/56 (45%); in 1/56 (2%) OMNISCAN 0.1 mmol/kg dose provided more diagnostic value and in 30/56 (54%)the cumulative OMNISCAN 0.3 mmol/kg dose provided more diagnostic value.

The relative usefulness of a single 0.3 mmol/kg bolus in comparison to the cumulative 0.3 mmol/kg (0.1 mmol/kg followed by 0.2 mmol/kg) has not been established.

OMNISCAN was evaluated in two double-blind, parallel studies with MAGNEVIST^® (gadopentetate dimeglumine) in a total of 173 children who were referred for CNS MRI. The children received either OMNISCAN or MAGNEVIST in a single 0.1 mmol/kg dose. OMNISCAN was administered to 84 children (45 boys and 39 girls) with a mean age of 8.9 (2-18) years; of these patients, 92% were Caucasian, 7% Black, and 1% other races. The demographics were similar for the 89 children who received MAGNEVIST. Postcontrast MRI results showed that added diagnostic information, diagnostic confidence, and new patient management information were provided in approximately 76%, 67% and 52%, respectively, of children who received OMNISCAN. These findings were similar to those of MAGNEVIST. CT or histopathology was performed in 70/173 (42%) children who received OMNISCAN and MAGNEVIST. Of these, 69/70 (98.6%) were confirmed.

OMNISCAN was evaluated in a controlled trial of 276 patients who were referred for MRI of the internal thoracic, abdominal, pelvic or retroperitoneal organs. These patients (170 men and 106 women) had a mean age of 57 (9-88) years. Patients received 0.1 mmol/kg OMNISCAN for imaging body areas that included the internal thorax (noncardiac), abdomen, and pelvis, or a dose of 0.05 mmol/kg for imaging the kidney. Pre- and post-OMNISCAN images were evaluated blindly for the degree of contrast, diagnostic value, and lesion detection. These were rated on a scale of remarkably improved, improved, no change, worse, and cannot be determined. The postcontrast results showed remarkably improved or improved diagnostic value in 90% of the thorax, liver, and pelvis patients, and in 95% of the kidney patients. These findings were similar to those of MAGNEVIST 0.1 mmol/kg.

In a dose ranging study of 258 patients who were referred for MRI of the internal thoracic, abdominal, pelvic, or retroperitoneal organs, the evaluated doses included OMNISCAN 0.025, 0.05, 0.1 mmol/kg. The lowest effective dose of OMNISCAN for the kidney was 0.05 mmol/kg.