A Clear, Mixed Nanomicellar Formulation of Voclosporin (LX214), Achieves Therapeutic Levels in Ocular Posterior Segment After Single and Multiple Topical Dosing in Rabbits

Abstract

Purpose: : Voclosporin (VCS), a next-generation calcineurin inhibitor, may be an effective treatment for ocular posterior segment diseases. The potential for topical ocular delivery of [¹⁴C]LX214 (0.2% [¹⁴C]VCS nanomicellar ophthalmic solution) to the posterior segment of the eye was evaluated by examining the pharmacokinetics (PK) of radioactivity in ocular tissues, fluids, and blood in New Zealand White (NZW; albino) and Dutch Belted (DB; pigmented) rabbits after topical ocular application.

Methods: : NZW (30 female/8 male) and DB (16 female) rabbits received topical 0.2% [¹⁴C]LX214 in one or both eyes as a single (NZW and DB) or daily (NZW) dose for up to 7 days. [¹⁴C]LX214-derived radioactivity was measured in multiple ocular tissues/fluids and in whole blood. VCS was also measured in whole blood by LC-API/MS/MS (LOQ; 0.100 ng/mL). PK parameters (C_max, T_max) for [¹⁴C]LX214 were determined for blood, tear, and ocular tissues, and for parent drug in blood.

Results: : After a single dose of [¹⁴C]LX214, C_max in the choroid/retina was 50 ng Eq/g (T_max 1 hr) in both NZW and DB rabbits; C_max in the optic nerve was 86 ng Eq/g (T_max 0.5 hr) in NZW and 199 ng Eq/g (T_max 1 hr) in DB rabbits, all well above the expected VCS therapeutic threshold of 30 ng Eq/g. After repeat dosing in NZW rabbits, choroid/retina and optic nerve VCS C_max was 79 ng Eq/g (T_max 2 hr) and 170 ng Eq/g (T_max 0.5 hr), respectively. Blood concentrations of VCS were low in NZW and DB rabbits after a single dose (C_max 1.73 and 1.28 ng/mL, respectively) at T_max’s of 1 hr and after multiple dosing in NZW rabbits (C_max was 1.16 ng/mL) at a T_max of 0.5 hr. There were no gender differences in ocular tissue or whole blood VCS levels.

Conclusions: : Single and multiple topical applications of 0.2% [¹⁴C]LX214 resulted in therapeutic VCS concentrations in the choroid/retina and optic nerve in both albino (NZW) and pigmented (DB) rabbit eyes, providing evidence of the potential for use of a topical nanomicellar drug delivery platform in the treatment of ocular posterior segment diseases.

Keywords: development • retina • optic nerve