Received for publication December 4, 2006.
Revised July 12, 2007.
Accepted for publication July 12, 2007.

Does linezolid inhibit its own metabolism? - Population pharmacokinetics as a tool to explain the observed nonlinearity in both healthy volunteers and septic patients

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^TM was performed in order to thoroughly understand the pharmacokinetics of unbound linezolid in plasma. Data was 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), a clearance CL (11.1 l/h), volumes of distribution V2 and V3 (20.0 and 28.9 l, respectively) and an 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 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 the respiratory chain enzyme activity. 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.

Key words: antibiotics, clinical pharmacokinetics, human pharmacokinetics, pharmacokinetic modeling, pharmacokinetics

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