Drug development studies supporting zileuton as a parenteral adjuvant to attenuate antibiotic-associated...

Glycopeptide, polymyxin, and aminoglycoside antibiotics are among the most commonly used agents to treat drug-resistant bacterial infections; however, their clinical use is hindered by nephrotoxicity. We previously reported that zileuton has the potential to attenuate antibiotic-associated nephrotoxicity in an animal model. Here, we further report the development of a parenteral formulation and exploration of dosing strategies for zileuton. The solubility, stability, and multi-dose safety of two zileuton formulations were evaluated. Zileuton serum and renal tissue pharmacokinetics were evaluated after a single dose and compared to steady state after 10 days. Different dosing strategies of zileuton to attenuate vancomycin-, polymyxin B-, and amikacin-associated nephrotoxicity were evaluated in rats over 10 days. Two formulations (1 and 10 mg/mL) showed good multi-dose safety, with no significant changes in serum creatinine, alanine transaminase, or body weight observed following doses of 12 mg/kg daily for 10 days. Zileuton was well-distributed into renal tissue, and serum exposure was comparable to humans after a typical dose (600-2,400 mg). No drug accumulation at steady state was observed. Zileuton was found to reduce nephrotoxicity associated with vancomycin, polymyxin B, and amikacin in a dose-dependent manner. With the same daily dose, dose fractionation resulted in similar renal protection compared to once-daily dosing. These preliminary studies support that zileuton has the potential to be used as a parenteral adjuvant to attenuate antibiotic-associated nephrotoxicity. This would allow the optimal use of glycopeptides, polymyxins, and aminoglycosides to treat difficult infections. Further studies are warranted to repurpose zileuton as a nephroprotectant.