Tolerability and Pharmacokinetics of Intravitreal Sirolimus

Abstract

Sustained i.v.t. delivery was achieved in a dose-dependent fashion after the i.v.t. injection of a proprietary sirolimus depot-forming ocular formulation. Across the tolerability and safety studies, no significant findings were observed for systemic and ocular tolerability. The human WB levels were well below the daily trough systemic blood level range required for systemic immunosuppression. An i.v.t. injection of sirolimus has a PK and safety profile that is favorable for treating inflammatory conditions of the eye, such as non-infectious uveitis, and warrants further investigation in humans.

In Vitro and In Vivo Sustained Zero-Order Delivery of Rapamycin (Sirolimus) From a Biodegradable Intraocular Device

“…A study using repeated injection of solubilized rapamycin in rabbit vitreous in vivo results in a dose-dependent concentration between 109 and 1050 ng/g at 4 weeks after injections, followed by a decline to approximately 20 ng/g by 8 weeks. 8 A study using a nanomicellar eye drop formulation achieved 362 6 56 (SEM), but was only measured at 1 hour after a single dose. 12 For our in vivo study, there was a large variability in the concentration of rapamycin measured in the retina-choroid for one device measured at week 4.…”

“…7 The injection is delivered directly into the vitreous, and treatment requires bimonthly injections for the duration of the chronic disease. 8,9 Intraocular administration of rapamycin in a small cohort of patients demonstrated no significant adverse effects, and levels of rapamycin in the blood were well below the concentration where systemic side effects occur. 8 Intraocular administration of rapamycin is a potential route for the treatment of posterior uveitis that bypasses the side effects associated with systemic administration.…”

“…8,9 Intraocular administration of rapamycin in a small cohort of patients demonstrated no significant adverse effects, and levels of rapamycin in the blood were well below the concentration where systemic side effects occur. 8 Intraocular administration of rapamycin is a potential route for the treatment of posterior uveitis that bypasses the side effects associated with systemic administration. Recent work has explored the use of silicon microparticles for the intravitreal delivery of rapamycin, but release kinetics appear to be limited to approximately 1 month.…”

“…In addition, zero-order drug release devices can maximize the effect of small drug payloads imposed by the size limits of the eye. Current administration techniques for rapamycin, such as eye drops 12 and injections, 8 fall short in their ability to achieve sustained drug concentrations in the eye over periods of a month or longer. The importance of long-duration rapamycin delivery is indicated by another mTOR inhibitor, everolimus, which in one study was shown to be effective in refractory uveitis, but uveitis returned in four of eight patients following the end of everolimus therapy.…”

The Effect of Transient Local Anti-inflammatory Treatment on the Survival of Pig Retinal Progenitor Cell Allotransplants

“…This dose of rapamycin has been shown to form a depot in the vitreous in a rabbit model and provides a therapeutic concentration for at least 1 month. 30 The half-life of dexamethasone is much shorter: It is cleared in less than 4 hours after intravitreal administration. 31 …”