Toward precision dosing of linezolid in critical ill patients: efficiency and risk of thrombocytopenia analysis by population PKPD modeling and simulations.

BACKGROUND AND

OBJECTIVE

In critically ill patients, determining the appropriate dose of linezolid requires pharmacokinetic data on the drug and an understanding of covariate effects on its disposition. However, previous studies has reported that the established population pharmacokinetic models demonstrate an unsatisfactory predictability when applied to external clinical settings. The aim of this study was to establish and evaluate a population pharmacokinetic and pharmacodynamic model for linezolid in critically ill patients.

METHODS

A total of 319 linezolid concentrations and 927 platelet counts were collected from 202 Chinese patients administered linezolid. Linezolid concentrations were quantified using a validated liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic and pharmacodynamic model was developed through nonlinear mixed-effects modeling. The established model was evaluated using bootstrap method, goodness-of-fit plots and visual predictive check. Based on the established model and identified covariates, an optimal dosing regimen was developed.

RESULTS

A one-compartment model with first-order absorption and elimination was developed to characterize the pharmacokinetics of linezolid. Creatinine clearance (CLcr) and Severe liver impairment (Child-Pugh C) were identified as the most significant covariates influencing clearance (CL). The typical values of CL and volume of distribution (Vd) in the final model were 2.03 L/h and 38.5 L, respectively. Both CLcr and fibrinogen levels demonstrated significant effects on baseline platelet count, while the area under the concentrations-time curve of linezolid exhibited a significant impact on mean transit time. Simulations based on the established population pharmacokinetic and pharmacodynamic model suggested that a reduced dose of linezolid 400 mg or 300 mg administered every 12 h could achieve the pharmacodynamic target while reducing thrombocytopenia risks in patients with CLcr <60 mL/min or severe liver impairment. Furthermore, the median time to thrombocytopenia onset was 12 days for patients with baseline platelet >200 × 109/L and 8 days for those with baseline platelet between 100 × 109/L and 200 × 109/L when receiving the standard dose of 1200 mg/day.

CONCLUSIONS

Critically ill patients, especially those with severe renal impairment or severe liver impairment, may necessitate a reduced linezolid dose to prevent overexposure. The established population pharmacokinetic and pharmacodynamic model could support individualized dosing optimization of linezolid in criticslly ill patients.