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

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. AUC(0-24h), C-max (0-24h) and Cmin 0-24h) were calculated. PK/TD relationships were assessed with Spearman's rank coefficient (r(s)) 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 R-2=0.97). Exposure-response relationships were found between AUC(0-24h) versus KIM-1 and osteopontin (R-2=0.61 and 0.66) and C-max (0-24h) versus KIM-1 and osteopontin (R-2=0.50 and 0.56) using a four-parameter Hill fit. Conversely, C-min (0-24h) was less predictive of KIM-1 and osteopontin (R-2=0.46 and 0.53). A vancomycin AUC(0-24h) 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 C-max rather than C-min. Further, an identified PK/TD target AUC(0-24h) of 482.2 mg.h/L may have direct relevance to human outcomes.