Pharmacokinetics and Pharmacodynamics of a Novel Dexamethasone Intravitreal Implant

Abstract

Purpose : Local drug delivery via surface erosion enables highly controlled, sustained release of drug. We have developed a novel approach to drug delivery in the eye that employs an erosion-based mechanism of drug release from a fully degradable, nonpolymeric implant. The lead product in development is an intravitreal implant (IBE-814 IVT) that releases dexamethasone to treat posterior inflammatory conditions. We have evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of the IBE-814 IVT implants in rabbits to demonstrate sustained dexamethasone release for ~6 months with implants delivered through a 30G needle.

Methods : PK of the IBE-814 IVT implants were tested in New Zealand white rabbits following intravitreal injection of the implants. Terminal time points of 1, 2, 8, 16, 26, and 40 weeks were used and drug was quantified in ocular tissues by LC/MS/MS. A rabbit VEGF-induced vascular leakage model was used to test the PD of IBE-814 IVT implants in inhibiting blood-retinal barrier breakdown. Dutch Belted rabbits underwent bilateral intravitreal injection on Day 0 and vascular leakage was induced by VEGF (1000 ng/eye) at 1, 10, and 26 weeks post-implantation. Inhibition of VEGF-induced vascular leakage was evaluated by fundus microscopy and fluorescein angiography. Commercially available dexamethasone implants were used as a control in both studies.

Results : The IBE-814 IVT implants released a low and consistent dose of dexamethasone (~6-15 ng/ml) in the vitreous humour of the rabbit eye out to at least 8 weeks, with later time points ongoing. In contrast, commercial dexamethasone implants had an initial burst release with no drug detected in the vitreous humor at week 8. The low, consistent dose of dexamethasone released from the IBE-814 IVT implants inhibited VEGF-induced vascular leakage at weeks 1 and 10 in the VEGF model as observed by fluorescein angiography. Commercial dexamethasone implants inhibited VEGF-induced vascular leakage at week 1 but not at week 10.

Conclusions : The IBE-814 IVT implant is a novel biodegradable surface-eroding implant delivered with a 30G needle that releases a low, consistent, and efficacious dose of dexamethasone out to at least 10 weeks in rabbits. Ongoing studies will assess drug release out to ~6 months.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

Drug in Vitreous Humour

 

Results of VEGF-Stimulation at 10 weeks