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Patricia B Williams, Frank A Lattanzio, Niaz Abdur-Rahman, R. Samuel English, Craig Greven; MINIMAL SYSTEMIC ABSORPTION AND ROBUST SAFETY PROFILE OF OC-10X, A VASCULAR DISRUPTING AGENT, AFTER TOPICAL APPLICATION IN NORMAL SUBJECTS. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4890.
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OC-10X, a quinazolinone is a selective tubulin inhibitor that disrupts abnormal cellular architecture and division. When administered precinically as a topical ophthalmic suspension, OC-10X demonstrated anti-angiogenic and angiolytic properties. This open label Phase 1 placebo controlled study assessed systemic distribution and tolerability of OC-10X eye drops.
After written informed consent, 10 subjects received 1 or 2% OC-10X ophthalmic suspension (OD) and vehicle (OS). Plasma samples were collected 1, 2, 4 and 24 hr after the first dose. OC-10X was then administered 4xd (QID) for 14 d with plasma collection on day 4, before and 1 hr after the first dose on day 14 and 24 hr after the last dose on day 14. Drug concentration was determined by a validated LC-MS/MS method (range 0.1 (LOD)-5.0ng/mL). Safety and tolerability were evaluated by ocular signs, symptoms, VA, IOP, biomicroscopy and ophthalmoscopy; systemic exposure by vital signs, ECG, clinical chemistry and CBC.
OC-10X was not detected in 63 of 90 samples, with only low amounts (0.1 - 0.64 ng/mL) in the remainder. After a single dose, OC-10X was mostly undetectable or near LOD. After repeated administration, measurable concentrations were consistently observed in two 1% OC-10X subjects (range 0.13-0.64ng/mL) and in two 2% OC-10X subjects (range 0.24-0.42ng/mL). 24 hr after the last dose, OC-10X was undetectable in all subjects. When detected, OC-10X plasma levels were not significantly different between 1% and 2% OC-10X subjects. All ocular and systemic safety parameters were normal, except for occasional mild corneal or conjunctival staining in both OC-10X and vehicle treated eyes.
Pharmacokinetic analysis indicates systemic absorption of topical OC-10X was low or undetectable. Both 1% OC-10X and 2% OC-10X ophthalmic suspensions were well tolerated when administered QID in healthy subjects. Minor, occasional ocular staining was likely due to the vehicle component benzalkonium chloride (BAK), known to cause this problem. Unlike other age-related macular degeneration (AMD) therapies, OC-10X is a topical vascular targeting agent without the traditional toxicity of this class. The robust OC-10X preclinical safety profile, now confirmed in this Phase 1 trial, provides the basis for initiation of Phase 2 clinical trials in AMD or proliferative diabetic retinopathy.
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