Population Pharmacokinetics Analysis and Dosing Simulations Of Meropenem in Critically Ill Patients with Pulmonary Infection.

PURPOSE: This study aimed to develop a population pharmacokinetic (PPK) model for meropenem to optimize dosing regimens for critically ill patients with pulmonary infection. PATIENTS AND METHODS: This prospective PPK study of meropenem was conducted on a pooled dataset of 236 blood samples obtained from 48 patients with pulmonary infection in the intensive care unit. Meropenem plasma concentrations were measured by a validated high-performance liquid chromatography-tandem mass spectrometry method, and the data were analyzed using NONMEM. The effect of covariates on meropenem pharmacokinetics was investigated. The probability of target attainment (PTA) to achieve the target of 100% fT>MIC at the proposed dosage regimens were investigated by Monte Carlo simulations. RESULTS: A two-compartment model adequately described the data with estimated glomerular filtration rate (eGFR) as a covariate significantly associated with the clearance (CL) from the central compartment. The typical value of CL was 7.48 L/h, with an eGFR adjustment factor of 0.0103 mL•1.73 m2/min, and the typical values of volume of the central compartment (V1), peripheral compartmental clearance (Q), and volume of the peripheral compartment (V2) were 15.9 L, 15.8 L/h, and 14.8 L, respectively. The goodness-of-fit plots, normalized prediction distribution error, and visual predictive checks showed good fitting and predictability of the final PPK model. When eGFR was >90 mL/min/1.73 m2, and there was a short duration of infusion (<60min), it was difficult for the probability target attainment (PTA) to reach >90% for MIC ≥ 2. Continuous infusion and frequent administration were necessary to achieve the target of 100% fT>MIC for critically ill patients with pulmonary infection. CONCLUSION: To achieve the optimal PTA, meropenem must be administered by frequent administration or continuously by an intravenous infusion. Our findings provide important information to optimize the meropenem regime in critically ill patients with pulmonary infection depending on eGFR values.

Pharmacokinetics of Linezolid Dose Adjustment for Creatinine Clearance in Critically Ill Patients: A Multicenter, Prospective, Open-Label, Observational Study.

PURPOSE: The aim of this study is to use a population pharmacokinetic (PK) approach to evaluate the optimal dosing strategy for linezolid (LNZ) in critically ill patients. METHODS: This multicenter, prospective, open-label, observational study was conducted in 152 patients, and 117 of them were included in the PK model, whereas the rest were in the validation group. The percentage of therapeutic target attainment (PTTA) comprising two pharmacodynamic indices and one toxicity index was used to evaluate dosing regimens based on Monte Carlo simulations stratified by low, normal, and high renal clearance for MICs of 0.25-4 mg/L. RESULTS: A single-compartment model with a covariate creatinine clearance (CrCL) was chosen as the final model. The PK parameter estimates were clearance of 5.60 L/h, with CrCL adjustment factor of 0.386, and a distribution volume of 43.4 L. For MIC ≤2 mg/L, the standard dosing regimen (600 mg q12h) for patients with severe renal impairment (CrCL, 40 mL/min) and standard dosing or 900 mg q12h for patients with normal renal functions (CrCL, 80 mL/min) could achieve PTTA ≥74%. The dose of 2400 mg per 24-h continuous infusion was ideal for augmented renal clearance (ARC) with MIC ≤1 mg/L. For MICs >2 mg/L, rare optimal dose regimens were found regardless of renal function. CONCLUSION: In critically ill patients, the standard dose of 600 mg q12h was sufficient for MIC ≤2 mg/L in patients without ARC. Moreover, a 2400 mg/day 24-h continuous infusion was recommended for ARC patients.