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

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.

Figure 1.

Randomization and animal dosing flowchart. TDD, total daily dose; ×1, once-daily dose.

Figure 2.

Best-fit plot for Bayesian observed versus predicted plasma vancomycin concentrations utilizing the final two-compartment model. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Exposure [AUC_0–24h (mg·h/L), C_{max 0–24h} (mg/L) and C_{min 0–24h} (mg/L)] versus urinary biomarkers KIM-1^a (a, b, c) and OPN^a (d, e, f) relationship by a four-parameter Hill model fit TD: four-parameter Hill model equation: Y = Bottom + (Top–Bottom)/{1 + 10^{[(log_EC50–X)×Hill Slope]}}. Data for clusterin are not shown as they did not show a strong relationship or correlation. ^aUnits for biomarker in ng/mL. Biomarker values were log₂ transformed and exposure values were log₁₀ transformed. EC₅₀, concentration at 50% of total biomarker increase. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.