Multicompartmental pharmacokinetic evaluation of enavogliflozin eye drop formulation: Understanding its distribution to posterior segments

Treating posterior segment diseases presents significant challenges because of the intricate anatomical and physiological barriers within the eye that limit drug penetration. Enavogliflozin eye drops (DWRX2008) are a novel candidate for diabetic retinopathy; however, their ocular distribution characteristics have not yet been identified. In this study, the ocular and systemic pharmacokinetics (PKs) of enavogliflozin were investigated using a multicompartmental PK model for DWRX2008.

Following topical instillation of a single dose of DWRX2008 (0.025 mg/eye) in both eyes of the rats, the concentration of enavogliflozin was quantified in five biological matrices (cornea, vitreous humor, retina, choroid, and plasma) using bioanalytical methods. A six-compartment model considering protein binding in the vitreous humor and systemic circulation was developed based on the disposition trends of eye drop formulations. The performance of the model was verified by visual inspection, fold-error, and sensitivity analyses.

Through this model, the peak concentration (C_max) and area under the curve from zero to infinity (AUC_0-∞) of enavogliflozin in retina were estimated at 39.51 ng/g and 151.12 ng∙h/g, respectively, indicating its reach to the target tissue. It was confirmed that enavogliflozin primarily follows the conjunctival-scleral pathway after topical instillation of eye drop formulations. The prolonged half-life of the drug in vitreous humor may be attributed to its interaction with the albumin present in the vitreous humor.

These findings established a scientific basis for the further development of enavogliflozin eye drops as a treatment for diabetic retinopathy.