24-Hour Pharmacokinetic Relationships for Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury [PublishAheadOfPrint]

Introduction: Vancomycin has been associated with acute kidney injury in preclinical and clinical settings, however the precise exposure profiles associated with vancomycin induced acute kidney injury has not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers.

Methods: Male Sprague-Dawley rats received clinical grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg/day were administered as single or 2 divided doses over a 24-hour period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained and urine was collected over the 24-hour period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin-c and neutrophil gelatinase-associated lipocalin were determined using MILLIPLEX MAP Rat Kidney Panels. Vancomycin plasma concentrations were determined via a validated HPLC methodology. Pharmacokinetic analyses were conducted using Pmetrics for R. Bayesian maximal a posteriori concentrations were generated and utilized to calculate 24-hour AUC, Cmax, and Cmin. Spearman's rho (r_s) was used to assess correlations between exposure parameters, biomarkers and histopathologic damage.

Results: Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker marker that correlated with both composite histopathologic damage (r_s=0.348, p=0.017) and proximal tubule damage (r_s=0.342, p=0.0.19). Vancomycin AUC and Cmax were most predictive of KIM-1 increases (r_s=0.438, p=0.002, r_s= 0.451, p=0.002, respectively).

Conclusions: Novel urinary biomarkers demonstrate that kidney injury can occur within 24 hours with vancomycin exposures, either as a function of AUC or Cmax.

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