Abstract |
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.
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Authors | C R Yates, A Vysokanov, A Mukherjee, T M Ludden, E Tolley, G U Meduri, J T Dalton |
Journal | Journal of clinical pharmacology
(J Clin Pharmacol)
Vol. 41
Issue 4
Pg. 415-24
(Apr 2001)
ISSN: 0091-2700 [Print] England |
PMID | 11304898
(Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Chemical References |
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Topics |
- Administration, Oral
- Adolescent
- Adult
- Aged
- Analysis of Variance
- Biological Availability
- Chromatography, High Pressure Liquid
- Double-Blind Method
- Female
- Humans
- Infusions, Intravenous
- Male
- Metabolic Clearance Rate
- Methylprednisolone
(administration & dosage, pharmacokinetics, therapeutic use)
- Middle Aged
- Models, Biological
- Protein Binding
- Respiratory Distress Syndrome
(drug therapy, metabolism)
- Time Factors
- Treatment Outcome
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