Ocular Pharmacokinetics/Pharmacodynamics of Besifloxacin, Moxifloxacin, and Gatifloxacin Following Topical Administration to Pigmented Rabbits

Purpose: The purpose of this investigation was to evaluate the ocular pharmacokinetic/pharmacodynamic (PK/PD) relationship for besifloxacin, moxifloxacin, and gatifloxacin using rabbit ocular PK data, along with in vitro minimum inhibitory concentration (MIC90) values against methicillin- and ciprofloxacin-resistant Staphylococcus aureus (MRSA-CR) and Staphylococcus epidermidis (MRSE-CR). Methods: Rabbits received a topical instillation of Besivance™ (besifloxacin ophthalmic suspension, 0.6%), Vigamox® (moxifloxacin hydrochloride ophthalmic solution, 0.5% as base), or Zymar® (gatifloxacin ophthalmic solution, 0.3%), and ocular tissues and plasma were collected from 4 animals/treatment/collection time at 8 predetermined time intervals during the 24 h after dosing. Ocular levels of each agent were measured by LC/MS/MS, and PK parameters (Cmax, Tmax, and AUC0–24) were determined. AUC0–24/MIC90 ratios were calculated for tears, conjunctiva, cornea, and aqueous humor using previously reported MIC90 values for MRSA-CR and MRSE-CR. Results: All of the fluoroquinolones tested demonstrated rapid penetration into ocular tissues after a single instillation. Besifloxacin demonstrated the highest exposure in tear fluid, while exposure in conjunctiva was comparable for all 3 compounds. Peak concentrations of all fluoroquinolones in aqueous humor were at or below ∼1 μg/mL. In comparison with their MIC90 values against MRSE-CR and MRSA-CR, besifloxacin achieved an AUC0–24/MIC90 ratio of ∼800 in tears, compared with values of ≤10 for moxifloxacin and gatifloxacin. In cornea, conjunctiva, and aqueous humor, the AUC0–24/MIC90 ratios were <10 for all compounds. However, in these tissues AUC0–24/MIC90 ratios for besifloxacin were 1.5- to 38-fold higher than moxifloxacin and gatifloxacin. Conclusions: In rabbits, besifloxacin demonstrates a nonclinical ocular PK profile characterized by high and sustained concentrations in tear fluid, resulting in AUC0–24/MIC90 ratios of ∼800 for ciprofloxacin-resistant MRSE and MRSA after a single administration. Although besifloxacin had the highest AUC0–24/MIC90 ratios for intraocular tissues, the ratios for all of the drugs were below the target values needed for effective bacterial killing of ciprofloxacin-resistant MRSE and MRSA. Taken together, these nonclinical data indicate that besifloxacin has a favorable ocular PK/PD profile, consistent with the reported clinical efficacy of besifloxacin in the treatment of bacterial conjunctivitis, and consistent with the profile needed for ocular surface sterilization.