{"doi":"10.1101/2020.08.27.270793","title":"The Pharmacodynamic-Toxicodynamic Relationship of AUC and CMAX in Vancomycin Induced Kidney Injury in an Animal Model","abstract":"ABSTRACT Background Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Methods Sprague-Dawley rats received IV vancomycin doses of 300mg/kg/day and 400mg/kg/day, divided once, twice, thrice or 4xdaily (i.e., QD, BID, TID or QID) over 24-hours. Up to 8-samples were drawn during the 24-hour dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via LC-MS/MS. Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e. AUC 0-24h , CMAX 0-24h ,) were calculated for each rat, and PK-TD relationships were discerned. Results A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed vs. predicted concentrations, R 2 =0.96). KIM-1 values were greater in QD and BID groups (P-values: QD vs TID:<0.002, QD vs QID:<0.004, BID vs TID:<0.002, and BID vs QID:<0.004). Exposure–response relationships were observed between KIM-1 vs CMAX 0–24h and AUC 0-24h (R 2 □=□ 0.7 and 0.68). Corrected Akaike’s information criterion showed CMAX 0-24h as most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (−5.28 versus −1.95). Conclusions While PK-TD indices are often inter-correlated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":122982,"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":0.915,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":565595,"name":"Gwendolyn Pais","orcid":null,"position":1,"is_corresponding":false},{"id":339321,"name":"Jiajun Liu","orcid":"0000-0002-4330-2098","position":2,"is_corresponding":false},{"id":298091,"name":"J. Nicholas O’Donnell","orcid":"0000-0001-5184-1385","position":3,"is_corresponding":false},{"id":298090,"name":"Thomas P. Lodise","orcid":"0000-0002-4730-0655","position":4,"is_corresponding":false},{"id":364681,"name":"Michael Neely","orcid":"0000-0002-1675-8276","position":5,"is_corresponding":false},{"id":507349,"name":"Walter C. Prozialeck","orcid":null,"position":6,"is_corresponding":false},{"id":565036,"name":"Peter C. Lamar","orcid":"0000-0002-5702-2257","position":7,"is_corresponding":false},{"id":565596,"name":"Leighton Becher","orcid":null,"position":8,"is_corresponding":false},{"id":339323,"name":"Marc H. Scheetz","orcid":"0000-0002-1091-6130","position":9,"is_corresponding":false},{"id":565035,"name":"Sean N. Avedissian","orcid":"0000-0002-0935-6455","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-18T23:14:55.385653Z","pmid":null,"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":[]}