The Pharmacodynamic-Toxicodynamic Relationship of AUC and C max in Vancomycin-Induced Kidney Injury in an Animal Model.
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Issue Date
2/17/2021
Authors
Avedissian, Sean N
Pais, Gwendolyn M
Liu, Jiajun
O'Donnell, J Nicholas
Lodise, Thomas P
Neely, Michael N
Prozialeck, Walter C
Lamar, Peter C
Becher, Leighton
Scheetz, Marc H
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Abstract
Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Sprague-Dawley rats received intravenous (i.v.) vancomycin doses of 300 mg/kg/day and 400 mg/kg/day, divided into once-, twice-, three-times-, or four-times-daily doses (i.e., QD, BID, TID, or QID) over 24 h. Up to 8 samples plus a terminal sample were drawn during the 24-h dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e., area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration from 0 to 24 h [C max0-24]) were calculated for each rat, and PK-TD relationships were discerned. A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed versus predicted concentrations; R (2) = 0.96). KIM-1 values were greater in QD and BID groups (P for QD versus TID, <0.002; P for QD versus QID, <0.004; P for BID versus TID, <0.002; and P for BID versus QID, <0.004). Exposure-response relationships were observed between KIM-1 versus C max0-24 and AUC0-24 (R (2) = 0.7 and 0.68). Corrected Akaike's information criterion showed C max0-24 as the most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (-5.28 versus -1.95). While PK-TD indices are often intercorrelated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.
Citation
Avedissian SN, Pais G, Liu J, O'Donnell JN, Lodise TP, Neely M, Prozialeck WC, Lamar PC, Becher L, Scheetz MH. The Pharmacodynamic-Toxicodynamic Relationship of AUC and Cmax in Vancomycin-Induced Kidney Injury in an Animal Model. Antimicrob Agents Chemother. 2021 Feb 17;65(3):e01945-20. doi: 10.1128/AAC.01945-20. PMID: 33318004; PMCID: PMC8092494.
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R15 AI105742/AI/NIAID NIH HHS/United States , R21 AI149026/AI/NIAID NIH HHS/United States