Work

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

Year: 2024

Type: article

Abstract: • VRP-034, a novel formulation of polymyxin B (PMB), exhibits significantly reduced nephrotoxicity compared with commercially available PMB in rats. • Similar plasma PMB concentrations and pharmacokinetic profiles were observed between VRP-034 and marketed PMB groups. • VRP-034 effectively mitigates PMB-induced kidney injury, as indicated by lower levels of kidney injury biomarkers, oxidative stress, inflammation markers and histopathological examination. • The composite measure of six novel urinary kidney injury biomarkers, evaluated through receiver operating characteristic curve analysis, demonstrates exceptional sensitivity, specificity and early detection capability, surpassing traditional kidney injury markers. This study assessed the nephrotoxicity and toxicokinetic profile of VRP-034 [a novel formulation of polymyxin B (PMB)] compared with marketed PMB over a 7-day repeat-dose regimen. Three objectives were pursued: evaluating PMB pharmacokinetics in both groups, alongside assessing the impact of VRP-034 on mitigating PMB-associated kidney injury; analysing the reversibility of kidney injury; and validating novel kidney injury biomarkers against traditional markers using histopathological scoring. Sixty-eight Sprague-Dawley rats were divided into three groups: 30 in each of the marketed PMB and VRP-034 groups, and eight in the control group. Rats received drugs at 6 mg/kg subcutaneously every 8 h (human equivalent dose ∼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 the remaining animals were observed for an additional 7 days without treatment. Samples were collected up to 12 h post-administration, followed by necropsy and histopathological examination. Plasma PMB concentrations were quantified; and kidney injury biomarkers, oxidative stress and anti-inflammatory markers were evaluated. Receiver operating characteristic curve analysis was performed to validate kidney injury biomarkers against histopathological grading. Similar plasma PMB concentrations and pharmacokinetic parameters were found in the two treatment groups. However, the VRP-034 group exhibited significantly lower nephrotoxicity, with reduced levels of kidney injury biomarkers, and diminished oxidative stress and inflammation levels compared with the 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 with marketed PMB, suggesting its potential as a safer alternative.

Source: International Journal of Antimicrobial Agents

DOI: 10.1016/j.ijantimicag.2024.107393