PD0325901, a Mitogen-Activated Protein Kinase Kinase Inhibitor, Produces Ocular Toxicity in a Rabbit Animal Model of Retinal Vein Occlusion

Abstract

This work has developed a rabbit model of PD0325901-induced RVO that may be used to characterize the cellular and molecular mechanisms of this effect in humans.

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

“…One limitation of the clinical development of PD-0325901 is that prolonged exposure can cause diarrhea and ocular toxicity (23)(24)(25); therefore, using the compound at a minimally effective dose rather than the maximum-tolerated dose may improve tolerability. This schedule was well tolerated, causing no weight loss over the treatment period (data not shown).…”

Retinal Vein Occlusion Induced by a MEK Inhibitor - Impact of Oxidative Stress on the Blood-Retinal Barrier

“…The retinal vascular toxicity was not observed in preclinical safety studies where PD0325901 was administered orally in rats and dogs for up to 13 weeks (Huang et al, 2009). The difference in the level of ocular toxicity between rabbits and rats/dogs could be attributed to ocular drug concentration differences arising from local vs. systemic routes of administration.…”

“…To develop an animal model of RVO to investigate mechanisms of toxicity, an in-life study was performed in rabbits, in which PD0325901 was administered by intravitreal injection at doses of 0.5 and 1 mg/eye, with an observation period of 2 weeks (Huang et al, 2009). The high dose was extrapolated to be a potentially toxic dose, while the low dose was chosen as a subtoxic dose, based on in vitro cytotoxicity data (Huang et al, 2009).…”

“…The high dose was extrapolated to be a potentially toxic dose, while the low dose was chosen as a subtoxic dose, based on in vitro cytotoxicity data (Huang et al, 2009). As early as 1 day after treatment, the high dose produced hemorrhages and vascular leakage with branch occlusion.…”

“…Through gene expression profiling analysis, we identified several mechanisms relevant to the development of RVO, including oxidative stress response, acute phase and inflammatory response, blood-retinal barrier (BRB) breakdown, leukostasis, and coagulation cascade (Huang et al, 2009). …”