Nonclinical Pharmacodynamics, Pharmacokinetics, and Safety of BOL-303224-A, a Novel Fluoroquinolone Antimicrobial Agent for Topical Ophthalmic Use

Abstract

BOL-303224-A is a novel fluoroquinolone that has never been used systemically and that possesses structural modifications intended to improve its potency compared to other fluoroquinolones. This investigation was conducted to evaluate the nonclinical pharmacokinetics, safety, and pharmacodynamics of BOL-303224-A. BOL-303224-A displayed activity in in vitro antimicrobial efficacy studies and also demonstrated efficacy in an in vivo murine infection model. BOL-303224-A demonstrated excellent ocular pharmacokinetics in rabbits, with ocular mean residence times >7 h, and conjunctival concentrations in excess of the MIC(90) for nonresistant ophthalmic isolates for >12 h following a single dose. Pharmacokinetic modeling from these data indicated that BOL-303224-A has the potential to demonstrate efficacy against ophthalmologic pathogens with a TID dosing regimen. BOL-303224-A also demonstrated reasonably low plasma protein binding in rat and human models, as well as good metabolic stability across species. In studies designed to explore the nonclinical safety profile of BOL-303224-A, the compound showed excellent topical ocular tolerance in rabbits and dogs, as well as a favorable genotoxicity and phototoxicity profile. In summary, BOL-303224-A exhibits an encouraging nonclinical pharmacodynamic, pharmacokinetic, and safety profile that supports clinical development as a topical agent for the potential treatment of ophthalmic infections.

Ocular Pharmacokinetics of Besifloxacin Following Topical Administration to Rabbits, Monkeys, and Humans

“…15 The penetration of besifl oxacin into cornea was evaluated using male Dutch-belted rabbits in the present investigation. Other study design considerations were consistent with the conduct of the previous reported study.…”

“…Other study design considerations were consistent with the conduct of the previous reported study. 15 Briefl y, each rabbit received a 50-μL instillation of besifl oxacin ophthalmic suspension (0.6%) into the conjunctival sac of each eye as a single bolus dose. At predetermined time intervals after dosing, rabbits (n = 4 per collection time) were euthanized and the eyes enucleated, frozen, and dissected, with tissues collected separately for each eye.…”

Besifloxacin in the management of bacterial infections of the ocular surface

“…30 Further, the C-8 chlorine substitution is thought to improve activity against organisms with DNA gyrase mutations. 31 Figure 2 depicts the chemical structures of several fluoroquinolones. In addition to point mutations in the bacterial genes encoding DNA gyrase and topoisomerase IV, efflux pumps may also mediate fluoroquinolone resistance.…”

Quantitative determination of besifloxacin, a novel fluoroquinolone antimicrobial agent, in human tears by liquid chromatography–tandem mass spectrometry

“…1) is a novel, chiral synthetic fluoroquinolone being developed by Bausch & Lomb for the topical treatment of ophthalmic infections. Structurally, besifloxacin has an N-1 cyclopropyl group, which provides broad-spectrum activity against aerobic bacteria [7]. The main mechanism of action of besifloxacin is the inhibition of both DNA gyrase and topoisomerase-IV enzymes that are involved in coiling and uncoiling of bacterial DNA.…”

“…The main mechanism of action of besifloxacin is the inhibition of both DNA gyrase and topoisomerase-IV enzymes that are involved in coiling and uncoiling of bacterial DNA. This activity is enhanced by a C-8 chloride substituent in besifloxacin, which also exhibits improved activity against gram-positive bacteria relative to older fluoroquinolones while still retaining potent efficacy against anaerobic bacteria [7].…”