1419. 24-Hour Pharmacokinetic Relationships for Intravenous Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury

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 to 400 mg/kg/day were administered as a single or twice daily injection over 24 hours. Controls received IV saline. Plasma sampling was conducted via a second dedicated catheter, with up to eight samples in 24 hours. 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 24 hours (i.e., AUC(0–24), C(MAX0–24), C(MIN0–24)) were calculated from Bayesian posteriors. PK-TD relationships were assessed with Spearman’s rank coefficient (r(s)) and the best fit mathematic model (e.g., exposure response curve fitting in GraphPad v.7). RESULTS: Forty-five vancomycin treated and five control rats contributed PK-TD data. A two-compartment model fit the data well (Figure 1: Population [a], Individual [b]). An exposure-response relationship was found between AUC(0–24) vs. KIM-1 (Figure 2a) and osteopontin (Figure 3a) and C(MAX24) vs. KIM-1 (Figure 2b) and osteopontin (Figure 3b) by four-parameter Hill fit. A weaker relationship was found for CMIN(0–24 hours) vs. KIM-1 (R(2) = 0.46) and less parity existed between PK measures and osteopontin, though AUC24 was best (R(2) = 0.66), all by four-parameter Hill fits. Spearman’s r(s) showed significant correlations between AUC(0–24) vs. KIM-1, AUC(0–24) vs. osteopontin and C(MAX0–24) vs. osteopontin (P < 0.001, r(s) = 0.53, r(s) = 0.75, r(s) = 0.65). CONCLUSION: Vancomycin induced kidney injury is most driven by AUC or C(MAX). Clinical monitoring should focus on C(MAX) and AUC and move away from trough only sampling. [Image: see text] [Image: see text] [Image: see text] DISCLOSURES: J. Liu, Merck: Grant fund from Merck, Research grant. W. Prozialeck, Midwetsren University: Collaborator, Grant recipient.