Toxicokinetic Insights are Critical to Understanding Renal Toxicity of Novel Polymyxin Analog

Abstract

Renal toxicity is the major dose-limiting toxicity for polymyxin antibiotics. Previous work in our labs has suggested that DMPK parameters play a modulatory role in the renal toxicity of polymyxin analogs. The goal of this study was to characterize the toxicokinetic (TK) profile of a novel polymyxin analog (“AZ TC”) versus the standard comparator compounds, colistin and polymyxin B (PMB). AZ TC was administered to male Wistar rats for 2 or 7 days of repeat dosing, subcutaneously. TK parameters were assessed at the end of the treatment period and at 14 days and 28 days following treatment cessation. TK analysis of plasma and terminal kidney homogenate samples was conducted, with MSI-MALDI evaluation of selected kidney samples. Additionally, renal toxicity was evaluated via clinical pathology, acute kidney injury (AKI) biomarker, macroscopic and microscopic observations. TK data demonstrated preferential and continued accumulation of AZ TC in kidney over the duration of dosing. Additionally, high levels of AZ TC were detected even during the recovery phase. Based on MSI data, accumulation appeared to be preferentially in the renal cortex. In conclusion, AZ TC elimination from the kidney appears to be slower than the comparators. These TK findings correlated to the renal toxicity profile of AZ TC, which, when compared to colistin and PMB, is relatively mild, but demonstrates a sustained duration of insult, as evidenced by histopathological and AKI biomarker data.