1419. 24-Hour Pharmacokinetic Relationships for Intravenous Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury. (26th November 2018)

• Record Type: Journal Article
• Authors: Avedissian, Sean; Liu, Jiajun; O'Donnell, J Nicholas; Pais, Gwendolyn; Becher, Leighton; Joshi, Medha; Prozialeck, Walter; Lamar, Peter; Lodise, Thomas P; Scheetz, Marc H
• Is Part Of: Open forum infectious diseases. Volume 5(2018)Supplement 1
• Page Start: S437
• Page End: S438
• Publication Date: 2018-11-26
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofy210.1250
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: 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., AUC0–24, 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 AUC0–24 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 CMIN0–24 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 AUC0–24 vs. KIM-1, AUC0–24 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. Disclosures: J. Liu, Merck: Grant fund from Merck, Research grant. W. Prozialeck, Midwetsren University: Collaborator, Grant recipient.