Ocular surface distribution and pharmacokinetics of a novel ophthalmic 1% azithromycin formulation.
OBJECTIVE
To investigate the ocular distribution of 1% azithromycin ophthalmic solution and the effect of polycarbophil-based mucoadhesive formulation on ocular tissue levels of azithromycin after single and multiple topical administrations in the rabbit eye.


METHODS
Rabbits were treated with either a single administration of 1% azithromycin solution with or without polycarbophil, or with multiple administrations of 1% azithromycin solution in polycarbophil. Drug concentrations were measured using LC/MS/MS. Conjunctiva, cornea, aqueous humor, and tear samples were analyzed over a period of 144 h after a single administration of azithromycin with or without polycarbophil. Eyelid, conjunctiva, cornea, aqueous humor, and tear samples were collected over a period of 288 h during and after multiple administrations of azithromycin.


RESULTS
Azithromycin was rapidly absorbed and distributed in the ocular tissues, reaching within 5 min, concentrations of 10,539 microg/mL in tear film, 108 microg/g in conjunctiva, and 40 microg/g in the cornea. The drug demonstrated tissue-specific half-lives of 15, 63, and 67 h, respectively. Following multiple administrations, the drug gradually accumulated. The polycarbophil formulation increased the bioavailability of the drug, producing peak concentrations that were between 5- and 12-fold higher than those without polycarbophil. Azithromycin also distributed rapidly in the eyelids, reaching peak concentrations of 180 mug/g at the end of the 7-day treatment, and was eliminated with a half-life of 125 h. Six days after treatment was discontinued, eyelid levels of azithromycin were above 40 microg/g.


CONCLUSIONS
Sustained and high concentrations were encountered with 7-day approved administration of 1% azithromycin formulation (AzaSite, Inspire Pharmaceuticals, Inc., Durham, NC) within all ocular surface tissues, particularly the lids. Many ocular surface disorders involving the tear film, eyelids, and adnexal structures are associated with chronic, low-grade bacterial infection and may potentially lead to decreased vision secondary to corneal scarring. Various topical antibiotic and steroid combinations with or without oral tetracyclines are commonly used with variable clinical response and known potential side effects. The clinical relevance of this study is unknown; however, the long-lasting antibacterial and additional anti-inflammatory properties of topical azithromycin might offer an effective alternative treatment option and should be explored further in clinical studies.
The Ocular Surface Diseases and Dry Eye Clinic, The Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Esen Karamursel
EK
Akpek
Jason
J
Vittitow
Rozemarijn S
RS
Verhoeven
Kurt
K
Brubaker
Thierry
T
Amar
Kendall D
KD
Powell
José L
JL
Boyer
Christopher
C
Crean
D000180:Acrylic Resins / Q000008:administration & dosage; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000378:metabolism; D017963:Azithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003228:Conjunctiva / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage; D006207:Half-Life; D013058:Mass Spectrometry; D009883:Ophthalmic Solutions; D011817:Rabbits; D013666:Tears / Q000378:metabolism; D014018:Tissue Distribution
D000180:Acrylic Resins; D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D009883:Ophthalmic Solutions; D017963:Azithromycin; C030312:calcium polycarbophil