title: Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats.
abstract: Vancomycin has been associated with acute kidney injury (AKI). However, the pharmacokinetic/toxicodynamic relationship for AKI is not well defined. Allometrically scaled vancomycin exposures were used to assess the relationship between vancomycin exposure and AKI. Male Sprague-Dawley rats received clinical-grade vancomycin in normal saline (NS) as intraperitoneal (i.p.) injections for 24- to 72-h durations with doses ranging 0 to 200 mg/kg of body weight divided once or twice daily. Urine was collected over the protocol's final 24 h. Renal histopathology was qualitatively scored. Urinary biomarkers (e.g., cystatin C, clusterin, kidney injury molecule 1 [KIM-1], osteopontin, lipocalin 2/neutrophil gelatinase-associated lipocalin 2) were assayed using a Luminex xMAP system. Plasma vancomycin concentrations were assayed by high-performance liquid chromatography with UV detection. A three-compartment vancomycin pharmacokinetic model was fit to the data with the Pmetrics package for R. The exposure-response in the first 24 h was evaluated using Spearman's nonparametric correlation coefficient (rs) values for the area under the concentration-time curve during the first 24 h (AUC0-24), the maximum concentration in plasma during the first 24 h (Cmax0-24 ), and the lowest (minimum) concentration in plasma after the dose closest to 24 h (Cmin0-24 ). A total of 52 rats received vancomycin (n = 42) or NS (n = 10). The strongest exposure-response correlations were observed between AUC0-24 and Cmax0-24 and urinary AKI biomarkers. Exposure-response correlations (rs values) for AUC0-24, Cmax0-24 , and Cmin0-24 were 0.37, 0.39, and 0.22, respectively, for clusterin; 0.42, 0.45, and 0.26, respectively, for KIM-1; and 0.52, 0.55, and 0.42, respectively, for osteopontin. However, no differences in histopathological scores were observed. Optimal sampling times after administration of the i.p. dose were 0.25, 0.75, 2.75, and 8 h for the once-daily dosing schemes and 0.25, 1.25, 14.5, and 17.25 h for the twice-daily dosing schemes. Our observations suggest that AUC0-24 or Cmax0-24 correlates with increases in urinary AKI biomarkers.
authors.affiliation: Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA.
authors.forename: Nathaniel J
authors.identifier: 0000-0002-0018-5434
authors.initials: NJ
authors.lastname: Rhodes
authors.affiliation: Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Illinois, USA.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Prozialeck
authors.affiliation: Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Lodise
authors.affiliation: Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Venkatesan
authors.affiliation: Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA.
authors.forename: J Nicholas
authors.initials: JN
authors.lastname: O'Donnell
authors.affiliation: Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA.
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Pais
authors.affiliation: Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Cluff
authors.affiliation: Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Illinois, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Lamar
authors.affiliation: University of Southern California, Keck School of Medicine, Los Angeles, California, USA Laboratory of Applied Pharmacokinetics and Bioinformatics (LAPKB), Children's Hospital of Los Angeles Saban Research Institute, Los Angeles, California, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Neely
authors.affiliation: Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Gulati
authors.affiliation: Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA mschee@midwestern.edu.
authors.forename: Marc H
authors.identifier: 0000-0002-1091-6130
authors.initials: MH
authors.lastname: Scheetz
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000652:urine*; D000818:Animals; D015415:Biomarkers / Q000652:urine*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D017207:Rats, Sprague-Dawley; D014640:Vancomycin / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D015415:Biomarkers; D014640:Vancomycin