Pharmacokinetics and Pharmacodynamics of a Single Oral Dose of Ascelia‐Manganese‐Based MRI Contrast Agent (ACE‐MBCA) in Adult Subjects With and Without Hepatic Impairment
Amit G. Singal, Eric Lawitz, Andreas Norlin, Nadilka Hettiarachchige, Thomas Bengtsson, Bachir TaouliABSTRACT
Background
Orally administered Ascelia‐manganese‐based contrast agent (ACE‐MBCA) is used for liver MRI, but its feasibility in patients with hepatic dysfunction remains unknown.
Purpose
To investigate the pharmacokinetics (PK), pharmacodynamics, and safety of ACE‐MBCA in subjects without/with hepatic impairment.
Study Type
Prospective, open‐label, sequential‐cohort study.
Population
Thirty‐five participants (mean age 56.5 years): 13 with normal hepatic function and 22 with liver disease, consisting of Child‐Pugh class A ( n = 9), B ( n = 6), and C ( n = 7).
Field Strength/Sequence
1.5 T, pre‐ and post‐contrast T1‐weighted gradient recalled‐echo.
Assessment
Liver signal intensity (SI) was measured on pre‐ and post‐contrast T1‐weighted images acquired 1, 4, 8, and 24 h after ACE‐MBCA administration. PK assessments included measured manganese concentrations in blood, plasma, urine, and feces over 72 h. PK parameters included AUC, C max , and T max . Adverse events were reported.
Statistical Tests
Non‐compartmental analysis was performed for PK parameters. Log‐transformed AUC and C max were compared using ANOVA. Changes in liver SI enhancement were analyzed using a mixed model. Significance was set at p ≤ 0.05.
Results
T max of manganese in blood ranged from 0.625 to 3.50 h. C max was 44.4 ng/mL in Child‐Pugh class C compared to 5.77 ng/mL in the normal group. C max increased by 25%–29% in normal/class A and 58%–61% in class B/C. AUC 0–24. It increased progressively with hepatic impairment, ranging from 38.4 h × ng/mL (normal) to 320 h × ng/mL (severe impairment). Liver SI peaked at 4 h and was significantly different among normal, mild, moderate, and severe hepatic impairment (45.8%, 35.1%, 18.9%, and 18.4%, respectively), while no difference was observed at 24 h ( p = 0.343). Mild to moderate gastrointestinal disorders were reported.
Data Conclusion
Peak liver enhancement occurred 4 h after a single oral dose of ACE‐MBCA in all groups, but its magnitude decreased and circulating manganese exposure increased with worsening hepatic function. The single dose of ACE‐MBCA was well tolerated.
Evidence Level
2.
Technical Efficacy
1.