Evaluation of Dose-Fractionated Polymyxin B on Acute Kidney Injury Using a Translational In Vivo Rat Model

Jiajun Liu; Gwendolyn M Pais; Sean N Avedissian; Annette Gilchrist; Andrew Lee; Nathaniel J Rhodes; Alan R Hauser; Marc H Scheetz

doi:10.1128/AAC.02300-19

Evaluation of Dose-Fractionated Polymyxin B on Acute Kidney Injury Using a Translational In Vivo Rat Model

Antimicrob Agents Chemother. 2020 Apr 21;64(5):e02300-19. doi: 10.1128/AAC.02300-19. Print 2020 Apr 21.

Authors

Jiajun Liu^{1

2

3}, Gwendolyn M Pais^{1

2}, Sean N Avedissian^{4

5}, Annette Gilchrist^{1

2

6}, Andrew Lee⁷, Nathaniel J Rhodes^{1

2

3}, Alan R Hauser⁶, Marc H Scheetz^{8

2

3}

Affiliations

¹ Midwestern University, Downers Grove, Illinois, USA.
² Midwestern University, Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, Illinois, USA.
³ Northwestern Memorial Hospital, Chicago, Illinois, USA.
⁴ Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC), Center for Drug Discovery, Omaha, Nebraska, USA.
⁵ University of Nebraska Medical Center, College of Pharmacy, Omaha, Nebraska, USA.
⁶ Northwestern University, Chicago, Illinois, USA.
⁷ Department of Chemical & Biological Engineering, Northwestern University, Evanston, Illinois, USA.
⁸ Midwestern University, Downers Grove, Illinois, USA mschee@midwestern.edu.

Abstract

We investigated dose-fractionated polymyxin B (PB) on acute kidney injury (AKI). PB at 12 mg of drug/kg of body weight per day (once, twice, and thrice daily) was administered in rats over 72 h. The thrice-daily group demonstrated the highest KIM-1 increase (P = 0.018) versus that of the controls (P = 0.99) and histopathological damage (P = 0.013). A three-compartment model best described the data (bias, 0.129 mg/liter; imprecision, 0.729 mg²/liter²; R², 0.652,). Area under the concentration-time curve at 24 h (AUC₂₄) values were similar (P = 0.87). The thrice-daily dosing scheme resulted in the most PB-associated AKI in a rat model.

Keywords: acute kidney injury; animal model; colistin; pharmacodynamic; pharmacokinetic; polymyxin B; polymyxins; toxicodynamic; urinary biomarker.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury / drug therapy*
Acute Kidney Injury / enzymology
Animals
Anti-Bacterial Agents / administration & dosage*
Anti-Bacterial Agents / pharmacokinetics
Anti-Bacterial Agents / therapeutic use*
Area Under Curve
Cell Adhesion Molecules / metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Kidney Function Tests
Male
Polymyxin B / administration & dosage*
Polymyxin B / pharmacokinetics
Polymyxin B / therapeutic use*
Rats
Rats, Sprague-Dawley
Translational Research, Biomedical

Substances

Anti-Bacterial Agents
Cell Adhesion Molecules
Havcr1protein, rat
Polymyxin B