Intracameral Conversion of Travoprost to Travoprost Acid in the Normotensive Beagle Dog Model

Abstract

 

Purpose

 

When dosed as an eye drop for the treatment of glaucoma, topical prostaglandin analogs (PGAs), such as travoprost, undergo conversion to their biologically active acid forms as they cross the cornea into the aqueous humor, making them bioavailable at the putative target tissues in the trabecular meshwork and uveoscleral pathway. It has been reported that some PGAs do not readily convert to the acid form in human aqueous humor alone. (Guerra, F.L., et al, ARVO 2012) The goal of this work was to determine if travoprost, delivered from a biodegradable, intracameral implant is readily converted to its active form in normotensive Beagle dogs.

 

Methods

 

Biodegradable implant formulations containing travoprost (25 to 40 μg) were fabricated using a proprietary PRINT® technology and administered intracamerally in beagle dogs. Aqueous humor samples were collected at 14, 28, and 60 days postdose and tested for travoprost ester and travoprost acid. The acid was quantified directly by LC/MS/MS. To measure the ester, samples were incubated in rabbit liver esterase and tested for total travoprost acid. The ester concentration was calculated by the difference in travoprost acid concentration before and after treatment.

 

Results

 

The lower limit of quantitation (LLOQ) for travoprost acid was determined to be 10 pg/mL. The mole fraction of the travoprost acid, relative to the overall mass balance of ester and acid, in the aqueous humor was significantly higher than that of the ester for all three implant formulations at all of the time points (0.8 to 1.0 at all timepoints; see figure).

 

Conclusions

 

Our results indicate conversion of the travoprost ester to travoprost acid when travoprost ester is directly administered to the anterior chamber from biodegradable PRINT-based intracameral implants. Given these findings, extended release intracameral PGA implants may offer an attractive solution to the shortcomings of the current topical PGAs used for the treatment of elevated IOP.

 

 

Figure 1. Relative mole fractions of travoprost acid and travoprost in Beagle aqueous humor at 14, 28, and 60 days post dosing with biodegradable, PRINT intracameral implants

 

Keywords: 568 intraocular pressure • 607 nanotechnology • 420 anterior chamber