Meropenem population pharmacokinetics and model-based dosing optimisation in patients with serious bacterial infection

Abstract

ObjectivesThe objective of this study was to develop a population pharmacokinetic model of meropenem in a heterogeneous population of patients with a serious bacterial infection in order to propose dosing optimisation leading to improved achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target.MethodsA total of 174 meropenem serum levels obtained from 144 patients during therapeutic drug monitoring were analysed using a non-linear mixed-effects modelling approach and Monte Carlo simulation was then used to compare various dosing regimens in order to optimise PK/PD target attainment.ResultsThe meropenem volume of distribution of the patient population was 54.95 L, while clearance started at 3.27 L/hour and increased by 0.91 L/hour with each 1 mL/s/1.73 m2 of estimated glomerular filtration rate. Meropenem clearance was also 0.31 L/hour higher in postoperative patients with central nervous system infection. Meropenem administration by continuous infusion showed a significantly higher probability of attaining the PK/PD target than a standard 30 min infusion (95.3% vs 49.5%).ConclusionsA daily meropenem dose of 3 g, 6 g and 10.5 g administered by continuous infusion was shown to be accurate for patients with moderate to severe renal impairment, normal renal function to mild renal impairment and augmented renal clearance, respectively.

Population pharmacokinetics, dosing optimization and clinical outcomes of biapenem in patients with sepsis

“…Although only a few studies have investigated the population pharmacokinetics of carbapenems in septic patients, an increase in the volume of distribution is common. Fukumoto et al revealed the volume of distribution of meropenem V (V 1 +V 2 ) in patients with sepsis was 39.7L (Fukumoto et al, 2023), while Murínová et al reported an average V of 55L in patients with serious infection (Murínová et al, 2022), respectively. Both studies reported higher V of meropenem in patients with sepsis comparing with other patients, which may be caused by the increase in V of hydrophilic drugs, which is quite common in critically ill patients (Roberts and Lipman, 2006).…”

“…Endotoxins induce the synthesis of various endogenous mediators, including cytokines, interleukins, and platelet-activating factor, can influence the vascular endothelium, leading to vasodilation, along with an aberrant distribution of blood flow, endothelial damage, and heightened capillary permeability. This syndrome results in fluid translocation from the intravascular compartment to the interstitial space, consequently increasing the Vd of water-soluble drugs, including carbapenems, and diminishing their serum concentrations (Murínová et al, 2022). It was reported that bipenem has a relatively short elimination half-life of approximately 1 hour.…”