Ocular metabolism and melanin binding properties of sunitinib, a dual VEGFR/PDGFR inhibitor, that can safely prolong its efficacy for the treatment of wet AMD

Abstract

Purpose : A proprietary depot formulation of sunitinib malate (SM)-loaded microparticles (GB-102) is in preclinical development as an intravitreal (IVT) injection product for the treatment of wet AMD. This work aims to characterize the in vivo release of sunitinib (S) from the depot, the biotransformation of S into a second, equally active moiety desethyl-S (D-S), and the sustained/reversible binding of S to melanin that can prolong the duration of active drug levels in retina and RPE-choroid (RC) following a single IVT injection of GB-102.

Methods : GB-102 (containing 1 mg SM) was dosed as an IVT injection (0.05 mL) in pigmented rabbits. Total S and D-S levels in R, RC, vitreous and in the depot itself were quantified by LC/MS/MS in samples taken from 1-7 months post-dose (PD). S binding to artificial melanin was evaluated in vitro to determine the proportion of free vs melanin-bound drug.

Results : By 2 to 3 months PD, 100% of SM in GB-102 is released from the depot. Peak levels of S in retina and RC at 3-month PD are ~10⁴x and ~10⁵x higher, respectively, than its K_i against VEGFR/PDGFR. Terminal elimination rate of S is 2-3 wks (retina) and 3-4 wks (RC), so that levels of S in retina and RC at 6-month PD remain ~10x and ~1000x higher than its K_i. The % ratio of D-S to S levels in retina is <1% (at 1-month PD) and 10-20% (at 6-7 months PD), indicating that D-S levels in retina are sufficient to contribute to pharmacologic activity at later time points. Approximately 0.1% of S exists as free drug in solution containing artificial melanin. Ocular modeling of the clearance of S, its biotransformation to D-S, and calculated levels of free S collectively support pharmacologically active levels in retina and RC for 5 to 6 months following a single GB-102 injection.

Conclusions : While all of the encapsulated SM is released from the GB-102 depot by 2-3 month post-dose in vivo, two properties of sunitinib can prolong its efficacy for an additional 3 months: Ocular biotransformation into a second active metabolite, and high-capacity, reversible binding to melanin in RPE-choroid as a secondary drug reservoir. These results support a potential twice per year dosing regimen of GB-102 for the treatment for wet AMD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.