Time-variant increase in methylprednisolone clearance in patients with acute respiratory distress syndrome: a population pharmacokinetic study

Methylprednisolone (MP) disposition was evaluated in 20 individuals who participated in an ongoing randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of MP in the treatment of acute respiratory distress syndrome (ARDS). MP (1 mg/kg) was given as a loading infusion over 30 minutes followed by a 1 mg/kg/day continuous i.v. infusion. Patients were switched to oral MP upon restoration of oral intake. MP plasma concentrations (n = 110) were determined using a specific HPLC method. Population pharmacokinetic analysis was performed using nonlinear mixed-effects models, implemented in NONMEM, version V. MP plasma concentration data were described by a one-compartment open model with a time-dependent, non-linear increase in the clearance (CL) of MP during the course of therapy. Initial clearance of MP (CLo) in ARDS patients at the start of therapy increased to a maximal value (CLmax) after approximately 7 days. The estimate of CLmax was similar to the CL of MP in healthy individuals reported previously. Population mean estimates (+/- SE) of parameters in the model were as follows: CLo = 13.2 +/- 2.4 L/h, CLmax = 25.0 +/- 3.6 L/h, time of half-maximal increase in CL (T50) = 41.1 +/- 8.2 h, gamma (Hill coefficient) = 3.8 +/- 0.6, and volume of distribution (Vd) = 137 +/- 30.2 L. Disease progression indices and patient demographics were evaluated as covariates, and no significant correlation was found. Means (+/- SD) of plasma protein binding differed between healthy individuals (72% +/- 4%) and ARDS patients (46% +/- 11%) (p < 0.001). The pharmacokinetics of MP in ARDS patients has not been described previously.