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.
Yates
C R
CR
University of Tennessee, Memphis, USA.
Vysokanov
A
A
Mukherjee
A
A
Ludden
T M
TM
Tolley
E
E
Meduri
G U
GU
Dalton
J T
JT
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008775:Methylprednisolone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D008954:Models, Biological; D011485:Protein Binding; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome
D008775:Methylprednisolone