Toxicokinetic Profiling of VRP-034: Evaluating its Potential in Mitigating Polymyxin B-Associated Nephrotoxicity.

Abstract

This study assessed the nephrotoxicity and toxicokinetic profile of VRP-034 (novel formulation of polymyxin B [PMB]) compared to marketed PMB over a seven-day repeat-dose regimen. Three objectives were pursued: evaluating PMB pharmacokinetics in both groups, alongside assessing VRP-034's impact on mitigating PMB-associated kidney injury; analyzing kidney injury reversibility; and validating novel kidney injury biomarkers against traditional markers using histopathology scoring. 68 Sprague-Dawley rats were divided into three groups: 30 each for marketed PMB and VRP-034 groups, and 8 for control. Animals received drugs at 6 mg/kg subcutaneously every 8 hours (HED ∼3 mg/kg/day). Toxicokinetic evaluations were conducted on selected animals on days 1, 2, 4 and 7 (after 3rd, 6th, 12th and 21st dose), while remaining animals were observed for an additional 7-days of treatment-free period. Samples were collected up to 12h post-administration, followed by necropsy and histopathological examinations. Plasma PMB concentrations were quantified; and kidney injury biomarkers, oxidative stress and anti-inflammatory markers were evaluated. Receiver operator characteristic curve analysis was performed to validate kidney injury biomarkers against histopathological grading. Results showed similar plasma PMB concentrations and pharmacokinetics parameters between both treatment groups. However, VRP-034 group exhibited significantly lower nephrotoxicity, with reduced kidney injury biomarkers levels, and diminished oxidative stress, and inflammation levels compared to marketed PMB group. Histopathological examination confirmed reduced renal damage in the VRP-034 group. Novel kidney injury biomarkers demonstrated superior sensitivity, specificity, and early detection capability over traditional markers. In conclusion, VRP-034 demonstrated reduced nephrotoxicity compared to marketed PMB, suggesting its potential as a safer alternative.