Population pharmacokinetic modeling and Monte Carlo simulation to optimize meropenem dosing in patients with severe...

Meropenem is commonly used to treat severe postoperative infections. However, substantial pharmacokinetic variability among surgical patients makes dose optimization challenging. Population pharmacokinetic (PopPK) modeling integrated with pharmacokinetic/pharmacodynamic (PK/PD) simulations may help support individualized dosing in this setting.

Adult patients with severe postoperative infections receiving meropenem were prospectively enrolled for therapeutic drug monitoring. Plasma meropenem concentrations were determined using a validated high-performance liquid chromatography (HPLC) assay. A nonlinear mixed-effects modeling approach was used to characterize meropenem pharmacokinetics and to explore potential covariates. Monte Carlo simulations (MCS) were performed to estimate the probability of target attainment (PTA) across different renal function categories and minimum inhibitory concentrations (MICs), using PK/PD targets of 40% fT > MIC, 100% fT > MIC, 50% fT > 4×MIC, and 100% fT > 4×MIC.

44 patients with 135 concentration measurements were analyzed. Meropenem pharmacokinetics were described by a one-compartment model with linear elimination. The typical population clearance (CL) and apparent volume of distribution (Vc) were 6.472 L/h and 26.69 L, respectively. Postoperative creatinine clearance (CRCL) was the only significant covariate affecting CL. Patients with augmented renal clearance or elevated MIC values may require intensified dosing strategies, whereas dose reduction is generally required in patients with renal impairment. For MIC ≤1 mg/L, 500 mg every 8 h achieved adequate PTA across most renal strata. At MIC 4 mg/L, intensified regimens (e.g., 1 g every 6-8 h or prolonged infusion) were required depending on renal function. At MIC 8 mg/L, even high-dose regimens were insufficient to achieve stringent PK/PD targets.

Postoperative renal function is a major determinant of meropenem exposure in patients with severe postoperative infections. PopPK-guided dosing combined with Monte Carlo simulation provides a practical framework for optimizing meropenem therapy and facilitating individualized antimicrobial treatment. Selecting dosing regimens according to renal function and MIC may improve the therapeutic effectiveness of meropenem in this population.