Analysis of pharmacokinetics of Gd-DTPA for dynamic contrast-enhanced magnetic resonance imaging

Abstract

The pharmacokinetics (PK) of the contrast agent Gd-DTPA administered intravenously (i.v.) for contrast-enhanced MR imaging (DCE-MRI) is an important factor for quantitative data acquisition. We studied the effect of various initial bolus doses on the PK of Gd-DTPA and analyzed population PK of a lower dose for intra-subject variations in DCE-MRI. First, fifteen subjects (23–85 years, M/F) were randomly divided into four groups for DCE-MRI with different Gd-DTPA dose: group-I, 0.1mmol/kg, n=4; group-II, 0.05 mmol/kg, n=4; group-III, 0.025mmol/kg, n=4; and group-IV, 0.0125 mmol/kg, n=3. Sequential fast T1 mapping sequence, after a bolus i.v. Gd-DTPA administered, and a linear T1-[Gd-DTPA] relationship were used to estimate the PK of Gd-DTPA. Secondly, MR-acquired PK of Gd-DTPA from 58 subjects (28–80 years, M/F) were collected retrospectively, from an ongoing study of the brain using DCE-MRI with Gd-DTPA at 0.025 mmol/kg, to statistically analyze population PK of Gd-DTPA. We found that the PK of Gd-DTPA (i.v. 0.025 mmol/kg) had a half-life of 37.3 ± 6.6 mins, and was a better fit into a linear T1-[Gd-DTPA] relationship than higher doses (up to 0.1 mmol/kg). The area under the curve (AUC) for 0.025 mmol/kg was 3.37± 0.46, which was a quarter of AUC of 0.1 mmol/kg. In population analysis, a dose of 0.025 mmol/kg of Gd-DTPA provided less than 5% subject-dependent variation in the PK of Gd-DTPA. Administration of 0.025 mmol/kg Gd-DTPA enable us to estimate [Gd-DTPA] from T1 by using a linear relationship that has a lower estimation error compared to a non-linear relationship. DCE-MRI with a quarter dose of Gd-DTPA is more sensitive to detect changes in [Gd-DTPA].

Contrast-enhanced MRI T1 Mapping for Quantitative Evaluation of Putative Dynamic Glymphatic Activity in the Human Brain in Sleep-Wake States

“…Given the small magnitudes of observed differences in peak DT1 and slope (2h-12h) in the cerebral and cerebellar GM and putamen, caveats regarding interpretation of the results should be noted. First, although the time-to-peak concentration at the superior and inferior sagittal sinus was only 2 minutes after intravenous GBCA injection (26), the possibility exists that the observed T1 value change over time could have been partly due to residual intravascular GBCA, given the mean terminal half-life of gadobutrol of 1.81 hours. Nonetheless, the facts that the observed slope (2h-12h) increased from day to night cycles in the cerebral and cerebellar GM and putamen, that the peak DT1 was higher in the cerebellar GM than in the cerebral GM, and that the cerebral and cerebellar WM, unlike the cerebral and cerebellar GM, showed only a small fluctuation in T1 values cannot be explained by the intravascular gadolinium effect alone, suggesting that another factor is likely dominant.…”

Iron Oxide Nanoparticles as T1 Contrast Agents for Magnetic Resonance Imaging: Fundamentals, Challenges, Applications, and Prospectives

“…[ 17,18 ] The Food and Drug Administration (FDA) has issued a number of warnings about the possible long‐term deposition of Gd in the brain, and the potential harms of this retention are under investigation. [ 19–21 ] The issues associated with the toxicity are further compounded by the short blood half‐life of GBCAs, [ 22–25 ] which may require patients to receive multiple contrast administrations to acquire necessary images. Clearly, there is an urgent need for a more biocompatible T 1 contrast agent.…”

Predictive Performance of Physiology‐Based Pharmacokinetic Dose Estimates for Pediatric Trials: Evaluation With 10 Bayer Small‐Molecule Compounds in Children

“…Gadovist and magnevist are both excreted primarily by glomerular filtration 38–40 . Therefore, the clearance of both contrast agents was predicted solely on the basis of knowledge about kidney maturation and developmental changes in GFR built in PK‐Sim.…”

“…Gadovist and magnevist are both excreted primarily by glomerular filtration. 38 , 39 , 40 Therefore, the clearance of both contrast agents was predicted solely on the basis of knowledge about kidney maturation and developmental changes in GFR built in PK‐Sim. The PBPK models for gadovist and magnevist that have been applied to support clinical decision making were updated to PK‐Sim version 9.0 before simulating the PK for each predefined pediatric age group.…”