Population Pharmacokinetic/Toxicodynamic Model for Polymyxin B in Critically Ill Patients to Identify the Risk of Nephrotoxicity
Year: 2025
Type: article
Study design: Observational Study
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 SCr 0 . Concomitant amikacin or vancomycin use resulted in increased sensitivity to polymyxin B. On day 21, Low ( f AUC 0–24 , SS = ~10 mg·h/L), medium ( f AUC 0–24,SS = ~20 mg·h/L ), and high ( f AUC 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.
DOI: 10.1002/cpt.3729
Authors: Patrick O. Hanafin, Ramya Mahadevan, Gauri G. Rao, Alexandre P. Zavascki, Ana Maria Sandri, Andrea Kwa, Marc H. Scheetz, Christine J. Kubin, Jayesh Shah, Benjamin P.Z. Cherng, Michael T. Yin, Jiping Wang, Lu Wang, David P. Calfee, Maureen Bolon, Anthony W. Purcell, Roger L. Nation, Jason M. Pogue, Jian Li, Keith S. Kaye
Institutions: University of North Carolina at Chapel Hill, University of Southern California, Universidade Federal do Rio Grande do Sul, Hospital Moinhos de Vento, Universidade Federal de Ciências da Saúde de Porto Alegre, Hospital São Lucas da PUCRS, Pontifícia Universidade Católica do Rio Grande do Sul, National University of Singapore, Singapore General Hospital, Duke-NUS Medical School, Midwestern University, NewYork–Presbyterian Hospital, Columbia University Irving Medical Center, Columbia University, Monash University, Weill Cornell Medicine, Northwestern University, Northwestern Memorial Hospital, University of Michigan, Rutgers, The State University of New Jersey
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,410
OpenAlex ID: W4411389902