Ocular pharmacokinetics of tivozanib eye drops in patients with neovascular age-related macular degeneration: comparison with phase 1 trials of oral tivozanib in solid tumors

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard treatment for neovascular age-related macular degeneration (nAMD) but is invasive and burdensome for patients. To overcome these obstacles, tivozanib, a pan-VEGF receptor inhibitor approved for renal cell carcinoma, is in development as eye drops. The phase 1 study of a 3-week administration of tivozanib eye drops showed a preferable safety profile and exploratory efficacy signs in Japanese patients with nAMD. During eye drop administration, two drug delivery pathways affect ocular pharmacokinetics, either directly through the ocular tissues or through systemic circulation. To assess the ocular pharmacokinetics of tivozanib eye drops, we conducted an integrated analysis of systemic adverse event occurrence and systemic exposure in patients with nAMD treated with tivozanib eye drops and in patients with cancer treated with oral tivozanib, using previous phase 1 study results. Systemic exposure was significantly lower with tivozanib eye drops versus oral tivozanib, with no drug-related hypertension due to the systemic pan-VEGF receptor inhibition observed, suggesting systemic VEGF receptors are not fully inhibited by tivozanib. Exploratory efficacy signs in patients with nAMD after short-term use of tivozanib eye drops also suggest tivozanib might reach the retina and inhibit VEGF receptors, although further long-term efficacy studies are warranted. Given the integrated analysis, we hypothesize that tivozanib eye drops could predominantly be delivered to the posterior eye segment through the ocular tissues, with limited contribution by the systemic drug delivery pathway. This hypothesis provides meaningful insights into the ocular pharmacokinetics of tivozanib eye drops.