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Toxicokinetic profiling of VRP-034: Evaluating its potential in mitigating polymyxin-B-associated nephrotoxicity

Kamlesh Vishwakarma1, Anmol Bisht1, Parveen Kumar1

  • 1Venus Medicine Research Centre, Bhatoli Kalan, Baddi, India.

International Journal of Antimicrobial Agents
|November 29, 2024
PubMed

Insights

VRP-034, a new polymyxin B (PMB) formulation, shows reduced kidney toxicity compared to standard PMB. This novel formulation may offer a safer alternative for patients requiring PMB treatment.

Area of Science:

  • Pharmacology and Toxicology
  • Nephrology
  • Biomarker Discovery

Background:

  • Polymyxin B (PMB) is crucial for treating multidrug-resistant Gram-negative bacterial infections.
  • PMB's use is limited by significant nephrotoxicity.
  • Novel formulations aim to mitigate PMB-associated kidney injury.

Purpose of the Study:

  • To compare the nephrotoxicity and toxicokinetic profile of VRP-034 with marketed PMB.
  • To evaluate the reversibility of kidney injury induced by PMB formulations.
  • To validate novel kidney injury biomarkers against traditional markers and histopathology.

Main Methods:

  • A 7-day repeat-dose study in Sprague-Dawley rats comparing VRP-034 and marketed PMB (6 mg/kg SC every 8 h).
  • Toxicokinetic evaluations, plasma drug concentration quantification, and assessment of kidney injury, oxidative stress, and inflammatory markers.
  • Histopathological examination and receiver operating characteristic (ROC) curve analysis for biomarker validation.

Main Results:

  • Similar plasma PMB concentrations and pharmacokinetic parameters were observed between groups.
  • VRP-034 group showed significantly lower nephrotoxicity, reduced kidney injury biomarkers, and diminished oxidative stress and inflammation.
  • Histopathology confirmed reduced renal damage in the VRP-034 group; novel biomarkers demonstrated superior detection capabilities.

Conclusions:

  • VRP-034 exhibits reduced nephrotoxicity compared to marketed polymyxin B.
  • The novel formulation demonstrates potential as a safer alternative to conventional PMB.
  • Novel kidney injury biomarkers offer improved sensitivity and specificity for early detection.
Keywords:
NephrotoxicityPolymyxin BVRP-034

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