Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model.
Loading...
Issue Date
2019-08
Authors
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
Degree
Advisor
Committee Members
Journal Title
Journal ISSN
Volume Title
Abstract
OBJECTIVES: To identify the pharmacokinetic (PK) and toxicodynamic (TD) relationship for vancomycin-induced kidney injury.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Citation
Avedissian SN, Pais GM, O'Donnell JN, Lodise TP, Liu J, Prozialeck WC, Joshi MD, Lamar PC, Becher L, Gulati A, Hope W, Scheetz MH. Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model. J Antimicrob Chemother. 2019 Aug 1;74(8):2326-2334. doi: 10.1093/jac/dkz167. PMID: 31065686; PMCID: PMC6640290.
ACPHS Research Commons URI
Description
Grants
R15 AI105742/AI/NIAID NIH HHS/United States