Does Linezolid Inhibit Its Own Metabolism?—Population Pharmacokinetics As a Tool to Explain the Observed Nonlinearity in Both Healthy Volunteers and Septic Patients

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 (K_A, 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.