title: 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.
authors.affiliation: Global Preclinical Development, Bausch & Lomb, Rochester, NY 14603, USA. Keith.W.Ward@bausch.com
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lepage
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Driot
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001381:Azepines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017484:Dermatitis, Phototoxic / Q000209:etiology; D004285:Dogs; D015817:Eye Infections / Q000188:drug therapy*; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009152:Mutagenicity Tests; D009883:Ophthalmic Solutions; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013535:Suspensions
chemical_list: D000890:Anti-Infective Agents; D001381:Azepines; D024841:Fluoroquinolones; D009883:Ophthalmic Solutions; D013535:Suspensions; C522124:besifloxacin