Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans.
OBJECTIVE
Studies were conducted to evaluate the ocular penetration and systemic exposure to besifloxacin, a fluoroquinolone antibiotic, following topical ocular administration to animals and humans.


METHODS
Besifloxacin ophthalmic suspension (0.6%) was administered as a topical ocular instillation to pigmented rabbits, cynomolgus monkeys, and human subjects. At predetermined intervals after dosing, samples of ocular tissues and plasma were collected and analyzed for besifloxacin levels using HPLC/MS/MS methods.


RESULTS
Besifloxacin demonstrated good ocular penetration in rabbits and monkeys, with rapid absorption and sustained concentrations observed in anterior ocular tissues through 24 h after a single administration. Maximum besifloxacin concentrations in conjunctiva, cornea, and aqueous humor of monkeys were 6.43 microg/g, 2.10 microg/g, and 0.796 microg/mL, respectively, after a single topical dose, and concentrations declined in these tissues with an apparent half-life of 5-14 h. Following a single topical ocular administration to humans, the maximum besifloxacin concentration in tears was 610 microg/g with concentrations decreasing to approximately 1.6 microg/g at 24 h. The resulting pharmacokinetic parameters for besifloxacin in human tears were evaluated relative to the MIC(90) values (microg/mL) for besifloxacin against Streptococcus pneumoniae (0.125), Staphylococcus aureus (0.25), Staphylococcus epidermidis (0.5), and Haemophilus influenzae (0.06). Following a single topical administration, the C(max)/MIC(90) ratios for besifloxacin in human tears were > or =1,220, and the AUC((0-24))/MIC(90) ratios were > or =2,500 for these relevant ocular pathogens. Following repeated 3-times daily (TID) topical ocular administration to human subjects with clinically diagnosed bacterial conjunctivitis, maximum besifloxacin concentrations in plasma were less than 0.5 ng/mL, on average.


CONCLUSIONS
Taken together, the results of the current investigation provide a PK/PD-based rationale that supports the use of besifloxacin for the safe and effective treatment of ocular infections.
Proksch
Joel W
JW
Global Research and Development, Bausch & Lomb, 1400 N. Goodman Street, Rochester, NY 14609, USA. Joel.W.Proksch@bausch.com
Granvil
Camille P
CP
Siou-Mermet
Raphaële
R
Comstock
Timothy L
TL
Paterno
Michael R
MR
Ward
Keith W
KW
D000287:Administration, Topical; D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000378:metabolism; D019540:Area Under Curve; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003228:Conjunctiva / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008826:Microbial Sensitivity Tests; D009883:Ophthalmic Solutions / Q000008:administration & dosage; D011817:Rabbits; D013045:Species Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods; D013666:Tears / Q000378:metabolism*; D014018:Tissue Distribution; D055815:Young Adult
D000900:Anti-Bacterial Agents; D001381:Azepines; D024841:Fluoroquinolones; D009883:Ophthalmic Solutions; C522124:besifloxacin