Population pharmacokinetics of polymyxin B in patients with liver dysfunction

Abstract Aims Polymyxin B (PMB) is widely used to treat infections caused by multidrug‐resistant Gram‐negative pathogens. Currently, the pharmacokinetic data of PMB in patients with liver dysfunction are limited. This study aimed to develop a population pharmacokinetic (PopPK) model of PMB in patients with liver dysfunction and identify the factors affecting PMB pharmacokinetics. Methods We conducted a retrospective pharmacokinetic study involving 136 adults with different levels of liver function. Nonlinear mixed effects modelling was used to develop a PopPK model of PMB. Monte Carlo simulation was used to design PMB dosage schedules across various liver and renal functions. Results PMB pharmacokinetic analyses included 401 steady‐state concentrations in 136 adult patients. A one‐compartment pharmacokinetic model with first‐order absorption and elimination was used to describe the data. The typical population value of PMB clearance was 2.43 L/h and the volume of distribution was 23.11 L. This study revealed that creatinine clearance (CrCL) and Child–Pugh class were significantly associated with PMB pharmacokinetic parameters; however, clinically relevant variations of dose‐normalized drug exposure were not significant. For patients with a minimum inhibitory concentration of ≤0.5 mg/L, the appropriate dose was 40–75 mg/12‐h. When the dose exceeded 100 mg/12‐h, the risk of nephrotoxicity increased significantly. Conclusions This study provided PMB pharmacokinetic information for patients with liver dysfunction. Patients with renal and liver dysfunctions may not require an initial dose adjustment. Rather than PopPK‐guided dose adjustment, therapeutic drug monitoring of PMB plays a more direct role in optimizing dosing regimens based on its therapeutic window.