**Background**
Diabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of visual impairment and blindness in middle-aged and elderly populations. Current treatments, such as intravitreal anti-VEGF injections, have limitations including frequent administration, high cost, and incomplete efficacy. Sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors, originally developed for type 2 diabetes, have shown potential in reducing retinal vascular permeability and oxidative stress. Enavogliflozin is a novel, selective SGLT2 inhibitor formulated as a topical ophthalmic solution (DWRX2008). This study aimed to characterize the ocular and plasma pharmacokinetics (PK) of enavogliflozin after single topical administration in preclinical species to assess its potential for treating diabetic retinal diseases.
**Methods**
Ocular distribution was evaluated in male New Zealand White rabbits (9 months old, 3.1–3.7 kg) after a single topical dose of 30 μL [14C]enavogliflozin (600 μg/eye, 1200 μg/head). Two rabbits were euthanized at each time point (0.5, 1, 2, 4, 8, 24, and 48 h post-dose), and heads were frozen and sectioned for autoradiography. Radioactivity concentrations were measured in conjunctiva, cornea, aqueous humor, iris, lens, sclera, vitreous body, retina, and optic nerve. Plasma PK was assessed in three independent groups: (1) rabbits (n=3) with serial blood collection for 48 h after ocular administration; (2) rabbits (n=14, 2 per time point) euthanized for both ocular and blood sampling; (3) additional rabbits (n=6) for ocular administration (400 μg/head, both eyes) and oral administration (400 μg/head). Plasma PK was also evaluated in male Brown Norway rats (n=3, 25 μg left eye) and male beagle dogs (n=3, 100 μg left eye). Enavogliflozin concentrations were measured by LC-MS/MS. PK parameters were calculated using noncompartmental analysis (Phoenix WinNonlin 8.3).
**Key Results**
After ocular administration in rabbits, the highest drug exposure was in the conjunctiva (Cmax 29,794.0 ng eq/g; AUC0–t 445,986.1 ng eq·h/g; half-life 20.7 h) and cornea (Cmax 10,725.8 ng eq/g; AUC0–t 104,518.8 ng eq·h/g; half-life 18.0 h). In the retina (target tissue), Cmax was 99.5 ng eq/g at Tmax 2 h, AUC0–t was 1594.2 ng eq·h/g, and half-life was 32.5 h. The vitreous body had low concentrations (Cmax 19.5 ng eq/g; AUC0–t 9.8 ng eq·h/g). Radioactivity was barely detectable in the optic nerve. Systemic exposure in rabbits showed plasma Cmax 17.6 ng eq/g at Tmax 1 h, AUC0–t 102.3 ng eq·h/g, and half-life 9.9 h. Whole blood concentrations were lower (Cmax 12.9 ng eq/g; AUC0–t 65.5 ng eq·h/g; half-life 5.7 h). In rats, plasma Cmax was 28.2 ng/mL at Tmax 4 h, half-life 5.4 h. In beagle dogs, plasma Cmax was 11.6 ng/mL at Tmax 1 h, half-life 10.6 h. Oral administration in rabbits resulted in much lower plasma exposure (Cmax 1.6 ng/mL; AUC0–t 8.7 ng·h/mL) compared to ocular administration (Cmax 19.3 ng/mL; AUC0–t 29.5 ng·h/mL). Retinal concentrations after oral administration were below the lower limit of quantification. The mean retina/plasma concentration ratios in rats at 1, 3, and 6 h were 3.3 (range 0.6–6.6), 1.3 (range 0.2–2.2), and 2.6 (range 1.4–3.3), respectively.
**Clinical Implications**
Topical enavogliflozin achieved therapeutic concentrations in the retina (above the IC50 for hSGLT2, 0.43 nM) for up to 24 h after a single dose, while systemic exposure remained low (plasma concentrations below IC50 values for hERG and other off-targets). The non-corneal (conjunctival/scleral) route appeared to contribute significantly to posterior segment delivery, as evidenced by higher AUC in conjunctiva and sclera compared to aqueous humor. The prolonged retinal half-life (32.5 h) suggests potential for once-daily dosing. These findings support further clinical development of DWRX2008 as a topical treatment for diabetic retinopathy and macular edema, offering a non-invasive alternative to intravitreal injections with reduced systemic side effects.