Ocular pharmacokinetics/pharmacodynamics of besifloxacin, moxifloxacin, and gatifloxacin following topical administration to pigmented rabbits.
OBJECTIVE
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 24h 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 MIC₉₀values 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 ~1g/mL. In comparison with their MIC₉₀values 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/MIC₉₀ratios 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.
Proksch
Joel W
JW
Global Pharmaceutical Research & Development , Bausch & Lomb, Incorporated, Rochester, NY 14609, USA. joel.w.proksch@bausch.com
Ward
Keith W
KW
D000287:Administration, Topical; D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects; D019540:Area Under Curve; D001372:Aza Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001381:Azepines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D003234:Conjunctivitis, Bacterial / Q000188:drug therapy; D005123:Eye / Q000187:drug effects*; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077734:Gatifloxacin; D006192:Haemophilus Infections / Q000188:drug therapy; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D011804:Quinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy; D013290:Streptococcal Infections / Q000188:drug therapy
D001372:Aza Compounds; D001381:Azepines; D024841:Fluoroquinolones; D011804:Quinolines; C522124:besifloxacin; D000077734:Gatifloxacin; D000077266:Moxifloxacin