{"doi":"10.1002/cpt.3729","title":"Population Pharmacokinetic/Toxicodynamic Model for Polymyxin B in Critically Ill Patients to Identify the Risk of Nephrotoxicity","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.","journal":"Clinical Pharmacology & Therapeutics","year":2025,"id":523650,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1396063,"name":"Ramya Mahadevan","orcid":"0009-0008-3951-1146","position":1,"is_corresponding":false},{"id":40493,"name":"Gauri G. Rao","orcid":"0000-0002-8704-7770","position":2,"is_corresponding":false},{"id":361330,"name":"Alexandre Prehn Zavascki","orcid":"0000-0001-5331-4837","position":3,"is_corresponding":false},{"id":1049032,"name":"Ana Maria Sandri","orcid":null,"position":4,"is_corresponding":false},{"id":345945,"name":"Andrea Lay‐Hoon Kwa","orcid":"0000-0001-8981-4411","position":5,"is_corresponding":false},{"id":339323,"name":"Marc H. Scheetz","orcid":"0000-0002-1091-6130","position":6,"is_corresponding":false},{"id":105378,"name":"Christine J. Kubin","orcid":"0000-0002-9819-440X","position":7,"is_corresponding":false},{"id":657558,"name":"Jayesh Shah","orcid":null,"position":8,"is_corresponding":false},{"id":1049033,"name":"Benjamin Pei Zhi Cherng","orcid":null,"position":9,"is_corresponding":false},{"id":105635,"name":"Michael T. Yin","orcid":"0000-0002-9346-9056","position":10,"is_corresponding":false},{"id":1396064,"name":"Jiping Wang","orcid":"0000-0003-2489-1074","position":11,"is_corresponding":false},{"id":1048354,"name":"Lu Wang","orcid":"0000-0003-3782-6642","position":12,"is_corresponding":false},{"id":445194,"name":"David P. Calfee","orcid":"0000-0002-4647-790X","position":13,"is_corresponding":false},{"id":1049034,"name":"Maureen Bolon","orcid":null,"position":14,"is_corresponding":false},{"id":287873,"name":"Anthony W. Purcell","orcid":"0000-0003-0532-8331","position":15,"is_corresponding":false},{"id":350711,"name":"Roger L. Nation","orcid":"0000-0003-1492-8590","position":16,"is_corresponding":false},{"id":226891,"name":"Jason M. Pogue","orcid":"0000-0003-4780-6215","position":17,"is_corresponding":false},{"id":258541,"name":"Jian Li","orcid":"0000-0001-7953-8230","position":18,"is_corresponding":false},{"id":232748,"name":"Keith S. Kaye","orcid":"0000-0003-2051-1732","position":19,"is_corresponding":false},{"id":916177,"name":"Patrick O. Hanafin","orcid":null,"position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:50:03.004175Z","pmid":"40524377","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}