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.

Vancomycin‐Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention

“…Intravenous studies, where careful control of exposures is possible and exposures are not compromised by variable absorption rates, have been used to probe the PK parameters that cause toxicity and quantitative thresholds for injury. Rat studies employing intravenous dosing have demonstrated that vancomycin AUC 0–24 or Cmax 0–24 , rather than minimum concentration (Cmin), predict urinary biomarker response 42–44 . A threshold AUC 0–24 of 482.2 mg·h/L has been identified and correlates directly with similar human exposure‐response data.…”

Evaluation of Dose Fractionated Polymyxin B on Acute Kidney Injury: A Translational In Vivo Model

“…First, our study was limited to 72-hour dosing compared to the relatively longer study period (up to 10 days) by Abdelraouf et al . The shorter time frame did not allow us to observe levels of plasma creatinine nor urinary biomarkers beyond this time frame; however, the urinary biomarkers utilized are highly sensitive in detecting early stages of AKI and our histopathology examinations confirmed the injury (30, 31, 46–48). Secondly, PB exposure (i.e.…”

“…that dose fractionated PB strategy led to more extensive AKI. Additionally, our study provided rich PK data to confirm the exposure status across experimental groups and employed highly sensitive and specific urinary biomarkers for early detection of AKI in addition to plasma creatinine (46). The level of injury was further confirmed by histopathological examination.…”

The Pharmacodynamic-Toxicodynamic Relationship of AUC and CMAX in Vancomycin Induced Kidney Injury in an Animal Model

“…Experimental methods and design were similar to those described previously. [7] Male Sprague-Dawley rats (N=53, approximately 8-10 weeks old, mean purchase weight 310g) were housed individually in a light and temperature-controlled room for the duration of the study and allowed free access to water and food. Rats (n=5-9 per dosing protocol) were administered IV injections of clinical-grade vancomycin (n=48) in normal saline (NS) or NS only (n=5, control) as previously described.…”

“…Preclinical rat studies have also found a consistent target, an AUC threshold of 482.2 has predicted 90% of maximal kidney injury biomarker response. [7] Thus, there is considerable evidence to support AUC as useful predictor of kidney injury, and thresholds are similar between humans and rats. It is still unknown if AUCs or maximal concentrations (Cmax) drives the toxicodynamic relationship for kidney injury.…”