Ocular pharmacokinetics of fluocinolone acetonide following Iluvien implantation in the vitreous humor of rabbits

Abstract

Purpose: The purpose of this study was to evaluate the systemic and ocular pharmacokinetics (PK) of fluocinolone acetonide (FAc) following administration of Iluvien(®) intravitreal implants.

Methods: The FAc intravitreal implant was administered to rabbits in 3 doses (0.2, 0.5, and 1.0 μg/day). The concentration of FAc was measured by a validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method in plasma and ocular tissues at various time points through month 24.

Results: Following administration of the 0.2 μg/day implant, FAc levels peaked in most tissues at day 2 or 8, reached approximate steady state levels by month 3 and very gradually decreased over the duration of the study. The FAc level in the aqueous humor was not measurable at most time points in the rabbit. FAc was still present in most ocular tissues at 2 years. The 0.5 and 1.0 μg/day dose groups followed the same pattern through month 9. The elimination half lives in the tissues for which it was measurable were greater than 83 days. Exposure to FAc was highest in the choroid/retinal pigment epithelium for all doses, followed by lens and retina.

Conclusions: The results of this study demonstrate sustained delivery of FAc from the Iluvien intravitreal implant in the ocular tissue of rabbits. Retina and lens FAc levels with the Iluvien implant were approximately 1/10 those reported with the Retisert(®) implant. FAc levels in the aqueous were not measureable with Iluvien where they were measured for 12 months with Retisert.

FIG. 1.

Fluocinolone acetonide (FAc) concentrations in ocular tissues following intravitreal administration of the FAc implant. Data reported in each panel represent the tissue concentrations (ng/g)±standard error of the mean for both eyes of 1 male and 1 female at each time point. (A) The levels of FAc in the vitreous humor and choroid/pigment epithelium were measurable for 2 years following the administration of one 0.2 μg/day implant. (B) The levels of FAc in the retina, vitreous humor, and choroid/pigment epithelium were measurable through month 9, when a second 0.5 μg/day implant was administered. (C) When 1.0 μg/day (two 0.5 μg/day implants) is administered on day 1, levels of FAc in the retina, vitreous humor, and choroid/pigment epithelium are approximately twice those observed with one 0.5 μg/day implant through month 9. When 2 additional 0.5 μg/day implants were administered at month 12, the FAc levels were similar to those after the first administration indicating that there was little accumulation. PE, pigment epithelium.

FIG. 2.

AUC_(0–tlast) in ocular tissues following intravitreal administration of the FAc implant. Based on the AUC_{(0–tlast) (ng*h/g)} exposure to FAc increased by dose as expected. The value for the low dose group is disproportionately smaller because this group received a single intravitreal implant on day 1 while the 0.5 and 1.0 μg/day groups received a second dose at month 12.