Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device.

ABSTRACT

PURPOSE: To determine the safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained drug delivery device. METHODS: Nonbiodegradable drug delivery devices containing 2 or 15 mg of a synthetic corticosteroid, fluocinolone acetonide, were constructed. The long-term in vitro release rates of these devices were determined in protein-free buffer or buffer containing 50% plasma protein. Fifteen-milligram devices were also implanted into the vitreous cavities of rabbit eyes. Intravitreal drug levels, the amount of drug remaining in explanted devices, and the release rate of explanted devices were determined over a 1-year time period. Drug toxicity was assessed over this same time period by slit lamp examination, indirect ophthalmoscopy, electroretinography, and histologic examination. RESULTS: The drug release rates for the 2-mg device, 1.9 +/- 0.25 microg/d, and for the 15-mg device, 2.2 +/- 0.6 microg/d, remained linear over the 6-month and 45-day testing period, respectively. The release rate increased by approximately 20% when devices were transferred from protein-free buffer to buffer that contained protein (P < 0.0001). Vitreous levels remained fairly constant (0.10-0.21 microg/ml) over a 1-year period. No drug was present in the aqueous humor during this time period. Based on the device release rates, the predicted life span of the 2- and 15-mg devices are 2.7 and 18.6 years, respectively. There was no evidence of drug toxicity by clinical examination, electroretinography, or histologic examination. CONCLUSIONS: It is feasible to construct a nontoxic fluocinolone acetonide drug delivery device that reproducibly releases fluocinolone acetonide in a linear manner over an extended period. These devices show great promise in the treatment of ocular diseases such as uveitis, which are often managed with chronic corticosteroid therapy.