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 par ticipated in an ongoing randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of MP in the treatment of acute respirato ry distress syndrome (ARDS). MP (1 mg/kg) was given as a loading infusion o ver 30 minutes followed by a I mg/kg/day continuous IV infusion. Patients w ere switched to oral MP upon restoration of oral intake. MP plasma concentr ations (n = 110) were determined using a specific HPLC method. Population p harmacokinetic analysis was performed using nonlinear mixed-effects models, implemented in NONMEM, version X MP plasma concentration data were describ ed by a one-compartment open model with a time-dependent, nonlinear increas e in the clearance (CL) of MP during the course of therapy initial clearanc e of MP (CLo) in ARDS patients at the start of therapy increased to a maxim al value (CLmax) after approximately 7 days. The estimate of CLmax was simi lar to the CL of MP in healthy individuals reported previously. Population mean estimates (+/- SE) of parameters in the model were as follows: CLo = 1 3.2 +/- 2.4 L/h, CLmax = 25.0 +/- 3.6 L/h, time of half-maximal increase in CL (T-50) = 41.1 +/- 8.2 h, gamma (Hill coefficient) = 3.8 +/- 0.6, and vo lume of distribution (Vd) = 137 +/- 30.2 L,. Disease progression indices an d patient demographics were evaluated as covariates, and no significant cor relation was found. Means (+/- SD) of plasma protein binding differed betwe en healthy individuals (72% +/- 4%) and ARDS patients (46% +/- 11%) (p < 0. 001). The pharmacokinetics of MP in ARDS patients has not been described pr eviously. <(c)> 2001 the American College of Clinical Pharmacology.