LAUSR

PURPOSE To evaluate saturation of piperacillin elimination in adult critically ill patients. PATIENTS AND METHODS Seventeen adult critically ill patients received continuous and intermittent infusion piperacillin/tazobactam. Piperacillin plasma concentrations (n=217) were analyzed using population pharmacokinetic (PopPK) modeling. Post hoc simulations were performed to evaluate the type I error rate associated with our study. Unseen data was used to validate the final model. The mean error (ME) and root mean squared error (RMSE) were calculated as a measure of bias and imprecision respectively. RESULTS A PopPK model with parallel linear and non-linear elimination best fitted our data. The median and 95% confidence intervals for model parameters drug clearance (CL), volume of the central compartment (V), volume of the peripheral compartment (Vp) and intercompartmental clearance (Q) were 9 (7.69 - 11) L/h, 6.18 (4.93 - 11.2) L, 11.17 (7.26 - 12) L and 15.61 (12.66 - 23.8) L/h. The Michaelis-Menten constant (Km) and the maximum elimination rate for Michaelis-Menten elimination (Vmax) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for Km and Vmax were 37.09 mg/L and 353.57 mg/h respectively. The ME was -20.8 (95% CI -26.2; -15.4) mg/L while imprecision (RMSE) was 49.2 (95% CI 41.2; 56) mg/L CONCLUSION: Piperacillin elimination is (partially) saturable. Moreover, the population estimate for Km lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients.