Daily fluid intake as a novel covariate affecting the population pharmacokinetics of polymyxin B in patients with sepsis

Polymyxin B dosing in patients with sepsis is difficult because pathophysiological changes and supportive therapies alter drug pharmacokinetics (PK). This study aimed to investigate the impact of fluid management and renal function on the PK of polymyxin B and to propose alternative dosing regimens. Patients (aged ≥ 18 y) with sepsis and receiving intravenous polymyxin B for ≥ 96 h were enrolled. Blood samples were collected at steady state. Plasma concentrations were measured by liquid chromatography-tandem mass spectrometry and subjected to population PK modelling. Monte Carlo simulations were used to optimise dosage regimens. Eighty-three patients with a median (range) daily fluid intake of 4.2 (1.3–8.4) L and a creatinine clearance (CrCL) of 87.5 (17.3–309.7) mL/min were included. Polymyxin B PK was adequately characterised by a two-compartment model. The PK covariate analysis revealed daily fluid intake statistically significantly affected central volume of distribution and central compartment clearance (CL), and CrCL influenced CL. Simulation indicated that a decreased dosing would be suitable for patients with renal dysfunction (CrCL < 40 mL/min), and therapeutic drug monitoring is recommended to avoid exposure fluctuation when patients have fluid overload. Fluid management as well as renal function are essential factors affecting polymyxin B PK for patients with sepsis, which can help optimise dosage regimens.