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 C_{min 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 R²"0.97). Exposure–response relationships were found between AUC_0–24h versus KIM-1 and osteopontin (R²"0.61 and 0.66) and C_{max 0–24h} versus KIM-1 and osteopontin (R²"0.50 and 0.56) using a four-parameter Hill fit. Conversely, C_{min 0–24h} was less predictive of KIM-1 and osteopontin (R²"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.