The pharmacodynamic-toxicodynamic relationship of auc and cmax in vancomycin-induced kidney injury in an animal model

Sean N. Avedissian, Gwendolyn Pais, Jiajun Liu, J. Nicholas O'Donnell, Thomas P. Lodise, Michael Neely, Walter C. Prozialeck, Peter C. Lamar, Leighton Becher, Marc H. Scheetz

Research output: Contribution to journalArticlepeer-review

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 300mg/kg/day and 400mg/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 [Cmax0-24]) 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; R2 = 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 Cmax0-24 and AUC0-24 (R2 = 0.7 and 0.68). Corrected Akaike's information criterion showed Cmax0-24 as the most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (25.28 versus 21.95). 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.

Original languageEnglish (US)
Article numbere01945-20
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

  • Pharmacodynamics
  • Pharmacokinetics
  • Pharmacology
  • Rat
  • Toxicodynamics
  • Vancomycin

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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