Abstract
Few studies investigating the population pharmacokinetics of linezolid in critically ill patients have been reported, yielding controversial results. Therefore, a population pharmacokinetic analysis using NONMEM was performed to thoroughly understand the pharmacokinetics of unbound linezolid in plasma. Data were obtained from 10 healthy volunteers and 24 septic patients. Intensive sampling was performed after single and multiple dosing. The pharmacokinetics of unbound linezolid was best described by a two-compartment model with an absorption rate constant (KA, 1.81 h-1), clearance (CL, 11.1 l/h), volumes of distribution (V2 and V3, 20.0 and 28.9 liters, respectively), and intercompartmental clearance Q, 75.0 l/h). However, clearance was inhibited over time to 76.4% of its original value, dependent on the concentration in an empirical inhibition compartment. Overall, imprecision of parameter estimates was low to moderate. Comparison of goodness of fit graphics and of the predictive performance revealed that the presented model was superior to previously published models using linear elimination or parallel linear and Michaelis-Menten elimination and also to other of our own investigated model alternatives. The observed nonlinearity in linezolid pharmacokinetics might be a result of an inhibition of the formation of the major linezolid metabolite due to the inhibition of respiratory chain enzyme activity. To our knowledge, this study presents the first attempt to mechanistically explain the observed nonlinearity in linezolid pharmacokinetics. Finally, simulations demonstrated that the model might also serve as a tool to predict concentration-time profiles of linezolid, thus providing a rationale for a more targeted antimicrobial therapy.
Footnotes
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Financial support: `Berliner Programm zur Foerderung der Chancengleichheit fuer Frauen in Forschung und Lehre', Berlin, Germany; the Dr. August and Dr. Anni Lesmueller foundation, Munich, Germany. Pharmacia is acknowledged for providing financial support for study materials.
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doi:10.1124/dmd.106.013755.
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ABBREVIATIONS: PK, pharmacokinetic(s); KA, absorption rate constant; CL, clearance; Q, intercompartmental clearance; OFV, objective function value; ALAG1, lag-time after oral dosing; RCLF, remaining CL fraction (i.e. noninhibitable fraction of CL); IIV, interindividual variability; KIC, rate constant into the inhibition compartment; IC50, concentration in the inhibition compartment yielding 50% of CL inhibition; Vmax, maximum elimination rate; Km, Michaelis-Menten constant.
- Received November 29, 2006.
- Accepted July 12, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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