A Systematic Review of Pharmacokinetic Studies of Colistin and Polymyxin B in Adult Populations.

Abstract

Background and objective: The pharmacokinetics of polymyxins are highly variable and conventional dosing regimens may likely lead to sub-optimal exposures and outcomes, particularly in critically ill patients with multi-drug-resistant infections. The aim of this systematic review is to describe the published pharmacokinetic data and to investigate variables that have been shown to affect the pharmacokinetics of colistimethate sodium, colistin, and polymyxin B in adult populations.

Methods: Sixty studies were identified. A total of 27 and 33 studies described the pharmacokinetics of colistin and polymyxin B, respectively.

Results: The most common dosing regimen for colistimethate sodium was a loading dose of 9 MIU, followed by 9 MIU/day in two to three divided doses, while for polymyxin B, a loading dose of 100-200 mg, followed by 50-100 mg every 12 h was given. Studies that used colistin sulfate instead of colistimethate sodium reported lower inter-individual variability, which may be attributed to the formulation of colistin sulfate being an active drug. The volume of distribution for colistin is typically lower in healthy individuals than in critically ill patients, owing to variations in physiological and pathological conditions. The clearance of colistimethate sodium in critically ill patients not undergoing dialysis was higher, around 13 L/h, compared with those receiving continuous renal replacement therapy, where clearance ranged from 2.31 to 8.23 L/h. In patients receiving continuous renal replacement therapy, clearance of colistin was higher compared with colistimethate sodium (2.06-6.63 L/h and 1.57-3.85 L/h, respectively). Colistin protein binding in critically ill patients ranged from 51% to 79%. The volume of distribution of polymyxin B was similar between critically ill and acutely ill patients, with range of 6.3-33.1 L and 6.22-38.6 L, respectively. Clearance of polymyxin B was also almost similar between critically ill and acutely ill patients (range of 1.27-2.32 L/h). There were two studies that reported free drug concentrations instead of the total drug concentrations of polymyxin B. In critically ill patients, protein binding ranged from 48.8% to 92.4% for polymyxin B. Creatinine clearance was the most common patient characteristic associated with altered clearance of colistimethate sodium and/or colistin, and polymyxin B.

Conclusions: Critically ill patients exhibit complex pharmacokinetics for colistin and polymyxin B, influenced by renal function, body weight, and clinical factors such as acute kidney injury, augmented renal clearance, serum albumin, and liver function. These factors necessitate individualized dosing adjustments to avoid toxicity and achieve therapeutic efficacy. Model-informed precision dosing provides a promising approach to optimize their use by integrating population pharmacokinetic parameters, patient-specific variables, and therapeutic drug monitoring, ensuring a balance between efficacy, safety, and resistance prevention.