International journal of antimicrobial agents · 2026
Population pharmacokinetics of polymyxin B in critically ill patients with multi-drug-resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa infections.
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Zamri Puteri Juanita, Wölky Saskia A, Hernandez-Mitre Maria P, Liu Xin, Hasan M Shahnaz, Shariff Izyani Md, Sulaiman Helmi, Wallis Steven C, Sumi Chandra Datta, Parker Suzanne L, Sime Fekade Bruck, Roberts Jason A, Abdul-Aziz Mohd Hafiz
Аннотация
OBJECTIVES: The aims of this study were to characterise the population pharmacokinetics (PK) of polymyxin B and to identify rational dosing strategies for Malaysian hospitalised patients.
METHODS: Enrolled patients received a polymyxin B loading dose of 2.5 mg/kg of total body weight (TBW) followed by a maintenance dose of 1.25-1.5 mg/kg TBW every 12 h. Serial blood samples were collected and assayed using validated ultra-high performance liquid chromatography-tandem mass spectrometry method. Population PK modelling and Monte Carlo dosing simulations were performed using Monolix.
RESULTS: Twenty-nine patients were included with a mean (SD) age of 51 (14) y old, TBW of 71 (22) kg, and estimated Cockcroft-Gault creatinine clearance of 68 (58) mL/min. A two-compartment model adequately described the data with TBW as a covariate for volume of distribution of central compartment. The population PK parameter estimates for drug clearance, volume of distribution of central compartment, volume of distribution of peripheral compartment, and inter-compartmental clearance were 1.6 L/h, 6.86 L, 10.76 L, and 11.97 L/h, respectively. Simulations showed that a fixed loading dose of 150 mg followed by a fixed maintenance dose of 75 mg every 12 h achieved optimal probability of target attainment against pathogens with an MIC of ≤1 mg/L and demonstrated the best balance between safety and efficacy for patients weighing 50-90 kg.
CONCLUSIONS: Our findings suggest that current weight-based dosing regimens recommended by International Consensus Guidelines may expose some patients to an increased risk of nephrotoxicity. A fixed-dose strategy (150 mg or 200 mg loading dose followed by 75 mg every 12 h) should be considered in this patient population.
METHODS: Enrolled patients received a polymyxin B loading dose of 2.5 mg/kg of total body weight (TBW) followed by a maintenance dose of 1.25-1.5 mg/kg TBW every 12 h. Serial blood samples were collected and assayed using validated ultra-high performance liquid chromatography-tandem mass spectrometry method. Population PK modelling and Monte Carlo dosing simulations were performed using Monolix.
RESULTS: Twenty-nine patients were included with a mean (SD) age of 51 (14) y old, TBW of 71 (22) kg, and estimated Cockcroft-Gault creatinine clearance of 68 (58) mL/min. A two-compartment model adequately described the data with TBW as a covariate for volume of distribution of central compartment. The population PK parameter estimates for drug clearance, volume of distribution of central compartment, volume of distribution of peripheral compartment, and inter-compartmental clearance were 1.6 L/h, 6.86 L, 10.76 L, and 11.97 L/h, respectively. Simulations showed that a fixed loading dose of 150 mg followed by a fixed maintenance dose of 75 mg every 12 h achieved optimal probability of target attainment against pathogens with an MIC of ≤1 mg/L and demonstrated the best balance between safety and efficacy for patients weighing 50-90 kg.
CONCLUSIONS: Our findings suggest that current weight-based dosing regimens recommended by International Consensus Guidelines may expose some patients to an increased risk of nephrotoxicity. A fixed-dose strategy (150 mg or 200 mg loading dose followed by 75 mg every 12 h) should be considered in this patient population.