Corneal Pharmacokinetics of Voriconazole and Posaconazole following Intrastromal Injection and Posaconazole Eye Drops Instillation in Rats

ABSTRACT Purpose/Aims: Infectious keratitis is a major cause of visual impairment and blindness worldwide. Common difficulties in treating fungal keratitis prompt new therapeutic possibilities. In this study, intrastromal voriconazole and posaconazole, and topical posaconazole were tested for their potential to obtain therapeutic cornea concentrations. Materials and Methods: Pharmacokinetics of triazole intracorneal/eye drop administration was studied in rats. Sixty-two rats were treated either by voriconazole or posaconazole. Twenty-nine and 33 rats received intrastromal injection of voriconazole solution (1 μl, 10 mg/ml) and posaconazole solution (1 μl, 18 mg/ml), respectively, administered under microscopic examination with a 32 gauge needle in the left cornea. Posaconazole (1.8% solution) eye drops were used. Cornea and plasma concentrations were determined using 2D HPLC separation and tandem MS, at 30 min, 3 h, 6 h, 24 h, 48 h, 72 h, and 144 h (6 days) post-intrastromal injection. The entire rat cornea was used for chromatography analyses. Results: In anesthetized rats, single intracorneal injection resulted, after 30 min, in respectively, >300 ng/mg and >260 ng/mg cornea concentrations, dropping to low levels within hours, while staying low in plasma. The effect of hourly posaconazole eye drops resulted in >10 ng/mg cornea concentration, which was maintained with instillations every 2 and then every 4 h. Conclusion: Our results show that there is little interest of intrastromal triazole administration due to the short duration of high cornea concentrations obtained after intracorneal injection. Posaconazole eye drops maintain therapeutic cornea concentrations in rats and could be used to treat severe infectious keratitis.