Population Pharmacokinetic/Toxicodynamic Model for Polymyxin B in Critically Ill Patients to Identify the Risk of Nephrotoxicity

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Abstract

Polymyxins are used against highly resistant Gram-negative pathogens, and nephrotoxicity (acute kidney injury, AKI) is the major dose-limiting adverse effect. We aimed to develop a well-informed population pharmacokinetic/toxicodynamic (PK/TD) model using the largest polymyxin B-treated critically ill patient population studied to inform polymyxin B dosing strategies. Critically ill patients receiving intravenous polymyxin B for at least 48 hours were enrolled in an observational study. Serum creatinine (SCr) concentrations were collected from electronic medical records. PK/TD analysis and Monte Carlo simulations were performed to determine the probability of AKI, P(AKI), for clinically relevant treatments. Patients (N = 117) aged 18-94 received intravenous polymyxin B (1.33-6.00 mg/kg/day) for 1-50 days. The changes in SCr were described using an indirect response model. The effects of polymyxin B-induced functional kidney injury were characterized using 9 transit compartments (mean time to onset ~7 days), leading to a reduction in SCr elimination. Sex was identified as a significant covariate for baseline SCr₀. Concomitant amikacin or vancomycin use resulted in increased sensitivity to polymyxin B. On day 21, Low (fAUC_0-24,_SS = ~10 mg·h/L), medium (fAUC_0-24,SS = ~20 mg·h/L ), and high (fAUC_0-24,SS = ~40 mg·h/L) drug exposures resulted in a P(AKI) (> 1-fold SCr increase) of 25.8%, 32.5%, and 40.4%, respectively. This study, the largest to date, suggests that regimens ranging from low to high polymyxin B exposures can minimize P(AKI) over a longer duration (14 days). However, supratherapeutic exposure can be administered relatively safely when limited to a shorter duration (≤ 4 days). The population PK/TD model may be used to improve polymyxin B dosing to help conserve this last-line agent.

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