Nonclinical ADME Studies of AG–013958 Demonstrate Sustained Ocular Exposure and Low Systemic Exposure

Abstract

Abstract: : Purpose: AG–013958 is in clinical development with sub–Tenon (ST) administration for treatment of choroidal neovascularization associated with age–related macular degeneration. Preclinical pharmacokinetic, distribution and metabolism studies of AG–013958 suggest sustained ocular exposure and low risk of metabolic liabilities for this VEGFR inhibitor. Methods: Tissue distribution of [¹⁴C]AG–013958 in pigmented rabbits was evaluated following ST or intravitreal (IVT) administration, with whole–body autoradiography (WBA) images taken up to 8 weeks. Systemic levels of AG–013958 were evaluated in rabbits and cynomolgus monkeys following ST, IVT or IV administration. WBA images were also taken following IV dosing to pigmented rabbits. In vitro metabolism of AG–013958 was conducted in human and rabbit liver microsomes. Cytochrome P450 (CYP) inhibition by AG–013958 was assessed in human liver microsomes using specific CYP probe substrates. Results: [¹⁴C]AG–013958 radioequivalents (req) did not distribute widely into tissues following ST or IVT injection. The majority of drug–related material at 8 weeks was present in the vitreous body (IVT dose) or depot region (ST dose) and other ocular tissues, particularly the pigmented tissues of the uvea. [¹⁴C]AG–013958 req in blood were below the limit of quantitation (0.02 µg–eq/g) from 24 hours to 8 weeks. WBA images after IV dosing demonstrated rapid biliary clearance and an affinity of [¹⁴C]AG–013958 req for melanin–rich tissues (skin and uvea). Plasma concentrations of AG–013958 after ST or IVT injection were below 0.2 ng/mL and the half–life after IV dosing was less than 2 hr. AG–013958 was minimally metabolized by CYP enzymes. AG–013958 inhibited CYP3A4, CYP2C8, CYP2C9 and CYP1A2 with IC₅₀ values of 1, 1.5, 10 and 11 µM, respectively. Plasma levels of 0.5 ng/mL or less, as predicted by low systemic exposure in nonclinical species and confirmed by early clinical data, would result in C_max–to–IC₅₀ ratios of less than 0.001 – well below the FDA risk guidelines for CYP–mediated drug interactions. Conclusions: WBA images of rabbit eyes following ST or IVT administration suggest an affinity of [¹⁴C]AG–013958 req for melanin–rich tissues and sustained exposure to ocular tissues for at least 8 weeks. The low systemic exposure of AG–013958 following ocular administration due to slow release from the site of administration and rapid systemic clearance suggests low risk for drug–drug interactions or systemic toxicities.

Keywords: age-related macular degeneration • choroid: neovascularization • metabolism