Population pharmacokinetics of polymyxin B in critically ill patients with multi–drug-resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa infections

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• This is the first study to characterise the population pharmacokinetics of polymyxin B in a hospitalised patient population in Malaysia and importantly, only the third reported study from Southeast Asia. • In this study cohort, 12 out of 29 patients demonstrated toxic polymyxin B concentrations (AUC ss,24h >100 mg·h/L) and nephrotoxicity was clinically observed in 4 patients with the current weight-based dosing regimens recommended by International Consensus Guidelines for the Optimal Use of Polymyxins. • Simulations showed that a fixed loading dose of 150 mg followed by a fixed maintenance dose of 75 mg every 12 hours 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 <90 kg, while a higher loading dose of 200 mg should be considered for those ≥90 kg. • Our findings suggest that current weight-based dosing regimens recommended by International Consensus Guidelines may expose some patients to an increased risk of nephrotoxicity. 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. 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 hours. 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. Twenty-nine patients were included with a mean (SD) age of 51 (14) years 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 hours 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. 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 hours) should be considered in this patient population.

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