Premium
Time‐Variant Increase in Methylprednisolone Clearance in Patients with Acute Respiratory Distress Syndrome: A Population Pharmacokinetic Study
Author(s) -
Yates Charles R.,
Vysokanov Alexander,
Mukherjee Arnab,
Ludden Thomas M.,
Tolley Elizabeth,
Meduri G. Umberto,
Dalton James T.
Publication year - 2001
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912700122010276
Subject(s) - pharmacokinetics , nonmem , medicine , ards , population , volume of distribution , methylprednisolone , anesthesia , placebo , respiratory distress , urology , gastroenterology , lung , alternative medicine , environmental health , pathology
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 IV 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, nonlinear increase in the clearance (CL) of MP during the course of therapy. Initial clearance of MP (CL 0 ) in ARDS patients at the start of therapy increased to a maximal value (CL max ) after approximately 7 days. The estimate of CL max was similar to the CL of MP in healthy individuals reported previously. Population mean estimates (± SE) of parameters in the model were as follows: CL 0 = 13.2 ± 2.4 L/h, CL max = 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 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.