Pharmacokinetic-pharmacodynamic modeling of manganese in patients with acute alcoholic hepatitis after an IV infusion of mangafodipir.
D. Hirt, F. Batteux, S. Urien, J.P. Richardet, P. Sogni, J. Poupon, A. Laurent, S. Pavlovic, M. Debray, J.M. Treluyer, B. Weill
Hôpital Cochin-Saint Vincent de Paul
Objectives: To determine pharmacokinetic profile of manganese after a 2 hours IV infusion of mangafodipir at 5 μmol/kg b.w., and to correlate manganese concentrations with oxidative stress, early decrease in bilirubin level (EDB) and prothrombin time (PT) in patient with acute alcoholic hepatitis.
Methods: Forty nine manganese concentrations were measured in 7 patients before, 15, 30, 45 minutes and 2, 7, 14 and 21 days after drug intake. A population pharmacokinetic model was developed in order to describe manganese concentration time courses and estimate inter-patients variabilities. The influence of individual characteristics was tested in the population model using a likelihood ratio test. Pharmacokinetics parameters were correlated to effects using Mann Whitney or Spearmann correlation unilateral tests. Fifty seven prothrombin times, reflecting liver activity, were measured in the 7 patients at days 1, 2, 7, 14, 21 and at months 1, 2, 3 and were used to build a pharmacodynamic model based on manganese concentrations.
Results: A two-compartment model with zero order absorption and first order elimination best described manganese data. Mean pharmacokinetic estimates and the corresponding inter-subject variabilities (%) were: clearance 27 L/h (36%), central volume of distribution 44 L, peripheral volume of distribution 1350 L, intercompartmental clearance 36.5 L (36%) and the endogenous manganese 15.8 nmol/L. AUC and Cmax were derived from the estimated individual pharmacokinetic parameters. AUC was significantly higher in patients who had an EDB. PT was correlated to an AUC increase at month 1. Concerning antioxidant status, plasma glutathion peroxydase significantly increased at day 2 when Cmax increased. PT evolution was best described by a signal transduction model with 2 transit compartments. Mean pharmacodynamic estimates and the corresponding inter-subject variabilities (%) were: intrinsic efficacy of the drug 142 nmol-1.L.s (51%) and mean transit time (Tho), 3.7 days (36%). When patient had an early decrease in bilirubin at day 7, Tho was increased to 27.3 days.
Conclusions: Manganese concentrations could be related to decrease in prothrombin time, the effect was longer in patients with an EDB than in others.