Pharmacokinetic-pharmacodynamic modeling of manganese after a single intravenous infusion of mangafodipir in patients with acute alcoholic hepatitis.

ABSTRACT

To determine the pharmacokinetic (PK) profile of manganese (Mn) after a 2-hour intravenous infusion of mangafodipir at 5 micromol/kg body weight and to correlate Mn concentrations with oxidative stress, early decrease in serum total bilirubin concentration, and prothrombin time (PT) in chronic alcoholic patients with acute alcoholic hepatitis. In 7 patients, a total of 49 serum Mn concentrations were determined on day 1 (before the start of the infusion and 15, 30, and 45 minutes after the end of the infusion) and on days 2, 7, 14, and 21. Fifty-seven PTs, reflecting liver activity, were measured on days 1, 2, 7, 14, and 21 and at months 1, 2, and 3. A population PK-pharmacodynamic model was developed to describe the kinetics of serum Mn concentrations and PT, to estimate interpatient variability, and to test covariate influence. A 2-compartment model with zero-order absorption and first-order elimination best described the data, and a signal transduction model with 2 transit compartments best described PT. Mean PK estimates and the corresponding interindividual variabilities (%) were clearance 23.1 L/h (34%), central and peripheral volume of distribution 35.4 and 1090 L, respectively, intercompartmental clearance 27.3 L (34%), endogenous Mn concentrations 15.8 nmol/L, slope-relating effect to concentration 141 nmol x L(-1) x s(-1) (52%), and mean transit time (tau) 3.8 days (34%). When patients had an early decrease in bilirubin at day 7, tau increased to 28.2 days. Serum Mn concentrations could be related to a decrease in PT; the effect was longer in patients with an early decrease in total bilirubin serum concentrations.