1568. The Pharmacodynamic–Toxicodynamic Relationship of AUC and CMAX in Vancomycin-Induced Kidney Injury

Abstract

Background

Vancomycin induces exposure-related acute kidney injury [AKI]; yet the toxicodynamic (TD) driver for toxicity (area under the curve [AUC], vs. maximum concentration [CMAX] vs. trough concentrations [CMIN]) remains unclear. Recent vancomycin guidelines now recommend monitoring AUC over troughs. Here we employed our translational rat model with intensive dose fractionation and sensitive FDA qualified urinary biomarkers to better understand TD relationship.

Methods

Male Sprague-Dawley rats received intravenous (IV) vancomycin via an internal jugular vein catheter. Total daily doses of 300 and 400 mg/kg/day were administered as a single, twice, thrice and four times a day injection over 24 hours. Controls received IV saline. Plasma sampling was conducted via a second dedicated jugular catheter, with up to 8 samples in 24 hours. Twenty-four-hour urine was collected during this time and assayed for kidney injury molecule 1 (KIM-1) and other urinary biomarkers using the MILLIPLEX MAP Rat Kidney Panel. Vancomycin in plasma was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. PK exposures during the first 24 hours (i.e., AUC_0-24hours, CMAX_0-24hours) were calculated from Bayesian posteriors. Pharmacokinetic-toxicodynamic (PK-TD) relationships were assessed with the best fit mathematic model (e.g., exposure-response curve fitting in GraphPad v.7).

Results

Sixty-four vancomycin treated and control rats contributed to PK-TD data. An exposure-response (via 4-parameter Hill) model was identified for AUC_0-24hoursvs KIM-1 (R² = 0.62, Figure 1a). Convergence was not obtained for exposure-response models for CMAX_0-24hours and CMIN, which was also verified visually (Figure 1b and c). Despite the intensive fractionation, AUC_0-24hoursand CMAX_0-24hours were highly correlated (P < 0.001, rho = 0.89) and this correlation was consistent across KIM-1 values (Figure 2).

Conclusion

Vancomycin-induced kidney injury was driven by AUC_{0-24 hours} and not CMIN. Continuous infusion studies are needed to understand if changing the infusion profile can improve safety; however, these studies suggest that isometric AUCs may result in similar toxicity. When using intermittent infusion schemes, clinicians should focus on AUC to prevent AKI.

Disclosures

All authors: No reported disclosures.

Session: 162. PK/PD and Susceptibility Testing

Friday, October 4, 2019: 12:15 PM