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Ayumi Yoshimatsu, Chiho Yabuta, Akira Ohtori, Mitsuyoshi Azuma; Transcorneal Delivery of FK962 is Altered by Flap Surgery in Rabbits. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3217.
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Creation of a corneal flap during laser in situ keratomileusis (LASIK) causes nerve degeneration and decreases corneal sensitivity, leading to dry eye and neurotrophic epitheliopathy. Pharmacokinetics modeling using in vitro transcorneal permeation studies provides useful predictions as to how topical application of drugs may be transported and accumulated by cornea. However, no data are available concerning pharmacokinetics modeling in corneas with flap surgery. Such data could be important in delivering drugs after LASIK surgery. In a previous study, FK962 promoted nerve regeneration and accelerated recovery of corneal sensitivity after flap surgery. Thus, the purpose of the present experiment was to test if flap creation influences transcorneal delivery of FK962, using in vitro and in silico modeling.
Corneas with or without flap creation were mounted side-by-side in an Ussing diffusion chamber. At predetermined time intervals, FK962 penetrating through cornea and accumulating in receptor cells was determined by HPLC at 225 nm. Diffusion and partition coefficients for FK962 across the cornea were calculated and used for in silico estimation of permeation of FK962 into living corneas.
FK962 permeated through corneas in the diffusion chamber and accumulated in receptor cells with increasing incubation times. Flap surgery caused slower permeation rates and lower accumulation of FK962. In pharmacokinetics modeling, a simulated, single topical application of 10-6 M FK962 (effective dose in vivo) caused peak concentrations of FK962 in the epithelium soon after application and stroma at 2 min, followed by gradual decreases. In contrast, 4 simulated applications of FK962 at 2-hour intervals caused persistence in cornea. Flap surgery also slowed the clearance of FK962 from cornea, suggesting longer accumulation in cornea.
Flap creation altered the transcorneal delivery of FK962. When determining dosing regimens for eye drops, the effect of LASIK surgery on specific drug uptake and clearance need to be considered and verified in vivo.
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