Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model


Avedissian, Sean N, Pais, Gwendolyn M, O'Donnell, J Nicholas, Lodise, Thomas P, Liu, Jiajun, Prozialeck, Walter C, Joshi, Medha D, Lamar, Peter C, Becher, Leighton, Gulati, Anil et al (show 2 more authors) (2019) Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 74 (8). pp. 2326-2334.

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Abstract

<h4>Objectives</h4>To identify the pharmacokinetic (PK) and toxicodynamic (TD) relationship for vancomycin-induced kidney injury.<h4>Methods</h4>Male Sprague-Dawley rats received intravenous (iv) vancomycin. Doses ranging from 150 mg/kg/day to 400 mg/kg/day were administered as a single or twice-daily injection over 24 h (total protocol duration). Controls received iv saline. Plasma was sampled with up to eight samples in 24 h per rat. Twenty-four hour urine was collected and assayed for kidney injury molecule 1 (KIM-1), osteopontin and clusterin. Vancomycin in plasma was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. PK exposures during the first 24 h (i.e. AUC0-24h, Cmax 0-24h and Cmin 0-24h) were calculated. PK/TD relationships were assessed with Spearman's rank coefficient (rs) and the best-fit mathematical model.<h4>Results</h4>PK/TD data were generated from 45 vancomycin-treated and 5 control rats. A two-compartment model fit the data well (Bayesian: observed versus predicted R2 = 0.97). Exposure-response relationships were found between AUC0-24h versus KIM-1 and osteopontin (R2 = 0.61 and 0.66) and Cmax 0-24h versus KIM-1 and osteopontin (R2 = 0.50 and 0.56) using a four-parameter Hill fit. Conversely, Cmin 0-24h was less predictive of KIM-1 and osteopontin (R2 = 0.46 and 0.53). A vancomycin AUC0-24h of 482.2 corresponded to a 90% of maximal rise in KIM-1.<h4>Conclusions</h4>Vancomycin-induced kidney injury as defined by urinary biomarkers is driven by vancomycin AUC or Cmax rather than Cmin. Further, an identified PK/TD target AUC0-24h of 482.2 mg·h/L may have direct relevance to human outcomes.

Item Type: Article
Uncontrolled Keywords: Plasma, Animals, Rats, Sprague-Dawley, Vancomycin, Cell Adhesion Molecules, Anti-Bacterial Agents, Chromatography, Liquid, Male, Clusterin, Osteopontin, Tandem Mass Spectrometry, Acute Kidney Injury, Administration, Intravenous, Biomarkers
Depositing User: Symplectic Admin
Date Deposited: 09 Apr 2020 10:33
Last Modified: 18 Jan 2023 23:56
DOI: 10.1093/jac/dkz167
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3081448
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