Evaluation of Long-Lasting Potential of Suprachoroidal Axitinib Suspension Via Ocular and Systemic Disposition in Rabbits

Abstract

Purpose Axitinib, a tyrosine kinase inhibitor, is a potent inhibitor of vascular endothelial growth factor (VEGF) receptors −1, −2 and −3. Suprachoroidal (SC) delivery of axitinib, combined with pan-VEGF inhibition activity of axitinib, has the potential to provide additional benefits compared to the current standard of care with intravitreal anti–VEGF-A agents. This study evaluated the ocular pharmacokinetics and systemic disposition of axitinib after SC administration in rabbits. Methods Rabbits received axitinib as either a single SC injection (0.03, 0.10, 1.00, or 4.00 mg/eye; n = 4/group) or a single intravitreal injection (1 mg/eye; n = 4/group) in three separate studies. Axitinib concentrations were measured in several ocular compartments and in plasma at predetermined timepoints for up to 91 days. The pharmacokinetics parameters were estimated by noncompartmental analysis. Results A single SC injection of axitinib suspension (1 mg/eye) resulted in an 11-fold higher mean axitinib exposure in the posterior eye cup, compared with intravitreal injection. Sustained levels of axitinib in the retinal pigment epithelium–choroid–sclera (RCS) and retina were observed throughout the duration of studies after a single SC axitinib injection (0.1 and 4.0 mg/eye), with low exposure in the vitreous humor, aqueous humor, and plasma. Axitinib levels in the RCS were 3 to 5 log orders higher than the reported in vitro (VEGF receptor–2 autophosphorylation inhibition) 50% inhibitory concentration value after 0.1 and 4.0 mg/eye dose levels throughout the 65-day and 91-day studies, respectively. Conclusions This study demonstrates that SC axitinib suspension has a favorable pharmacokinetics profile with potential as a long-acting therapeutic candidate targeted to affected choroid and retinal pigment epithelium in neovascular age-related macular degeneration. Translational Relevance Suprachoroidal axitinib suspension has potential to decrease the treatment burden in neovascular age-related macular degeneration, as a long-acting therapeutic candidate, and could yield greater efficacy, as a potent tyrosine kinase pan-VEGF inhibitor, compared with current standard anti-VEGF-A therapies.

Microinjection via the suprachoroidal space: a review of a novel mode of administration

“…4,21 Moreover, the structure of the SCS enables a degree of drug sequestration away from the iris/ciliary body, lens, and aqueous humor, thereby limiting drug exposure to anterior tissues. 7,8,22 Previous methods of accessing the SCS often required an operating room setting with immobilization of patient's eye under anesthesia and surgical dissection through the sclera. 4 The SCS Microinjector ® was designed specifically to access the SCS safely and easily using only local anesthesia.…”

“…4 In a rabbit model, SCS injection of a solution containing micronized axitinib compounded with a wetting agent, a tonicity agent, and a viscosity-enhancing agent resulted in much greater drug exposure in the retina, choroid, and posterior sclera and substantially decreased drug exposure in the vitreous humor vs IVT injection. 7 After SCS injection, axitinib levels in the plasma and aqueous humor were undetectable. The utility of the SCS as a location for drug administration was further confirmed by the observation that a single SCS injection produced sustained and high levels of axitinib in the RPE-choroid-sclera (RCS) and retina.…”

“…22 In animal models, drugs injected into the SCS were undetectable in the aqueous humor and had negligible dissemination into the vitreous as compared with those given via IVT injection. 7,8 Because of this compartmentalization of administered drugs away from the anterior segment of the eye, SCS delivery may decrease the risk of some AEs associated with drug exposure to the anterior chamber, such as elevations in IOP and development or progression of cataracts associated with corticosteroid use. 4,15 Until recently, therapeutic access to the SCS generally has required surgical dissection through the sclera in the operating room with the target eye anesthetized and immobilized.…”

“…After 6 months, in a separate rabbit toxicology study, mean axitinib levels in the RCS and in the retina were 3 to 5 log orders higher than the in-vitro concentration of an agent needed to inhibit VEGF receptor 2 by 50%, further supporting the potential for long-acting drug delivery to posterior segment tissues through SCS injection. 7 Additionally, a series of studies in rabbits compared drug distribution following IVT and SCS injection of the TA injectable suspension formulation Triesence (TRI; FDA approved for uveitis and several other ocular diseases) and following SCS injection of 2 different TA formulations, including TRI and an investigational prototype of a TA injectable suspension for use in the SCS (X-TA). 8,30 In the first of these 2 studies, 50 rabbits received TRI as bilateral IVT injections or as bilateral SCS injections to compare drug concentrations in ocular tissues and plasma after drug delivery.…”

“…[1][2][3][4][5][6] For diseases affecting the posterior tissues of the eye, SCS administration offers compartmentalization of therapies away from anterior tissues and the potential for long-acting delivery to target tissues. 7,8 One disease that can affect posterior tissues and that is associated with considerable visual impairment is uveitis, which is characterized by inflammation of the uveal tract (ie, iris, ciliary body, and choroid) and adjacent structures. 1,3,9 Uveitis can result from either infectious or noninfectious (eg, autoimmune) processes.…”