Background: Vancomycin induces exposure-related acute kidney injury; yet only troughs are generally monitored in patients. In rat models, intraperitoneal dosing results in highly variable drug exposures. Thus, intravenous (IV) vancomycin was used to assess pharmacokinetic-toxicodynamic (PK-TD) relationships with nephrotoxicity.
Methods: Male Sprague-Dawley rats received IV vancomycin via an internal jugular vein catheter. Total daily doses ranging from 150 mg/kg/day to 400 mg/kg/day were administered as a single or twice daily injection over 24 hours (h). Controls received IV saline. Plasma sampling was conducted via a 2nd dedicated catheter, with up to 8 samples in 24h. Twenty-four-hour urine was collected during this time and assayed for kidney injury molecule 1 (KIM-1), osteopontin (OPN) and clusterin 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 24h (i.e. AUC0-24, CMAX0-24, CMIN0-24) were calculated from Bayesian posteriors. PK-TD relationships were assessed with Spearmans rank coefficient (rs) and the best fit mathematic model (e.g. exposure response curve fitting in GraphPad v.7).
Results: Forty-five vancomycin treated and 5 control rats contributed PK-TD data. A 2-compartment model fit the data well (Figure 1: Population [a], Individual [b]). An exposure-response relationship was found between AUC0-24 vs KIM-1 (Figure 2a) and osteopontin (Figure 3a) and CMAX24 vs KIM-1 (Figure 2b) and osteopontin (Figure 3b) by 4-parameter Hill fit. A weaker relationship was found for CMIN0-24h vs KIM-1 (R2=0.46) and less parity existed between PK measures and osteopontin, though AUC24 was best (R2=0.66), all by 4-parameter Hill fits. Spearmans rs showed significant correlations between AUC0-24 vs. KIM-1, AUC0-24 vs. osteopontin and CMAX0-24 vs. osteopontin (p<0.001, rs=0.53, rs=0.75, rs=0.65).
Conclusion: Vancomycin induced kidney injury is most driven by AUC or CMAX. Clinical monitoring should focus on CMAX and AUC and move away from trough only sampling.
J. N. O'Donnell, None
G. Pais, None
L. Becher, None
M. Joshi, None
W. Prozialeck, Midwetsren University: Collaborator , Grant recipient .
P. Lamar, None
T. P. Lodise Jr., None
M. H. Scheetz, None