Work

Physiologically-based pharmacokinetic modeling of enavogliflozin ophthalmic solution for starting dose selection in diabetic retinopathy treatment

Year: 2025

Type: article

Abstract: The ophthalmic solution of enavogliflozin has been developed to treat diabetic retinopathy by inhibiting the sodium-glucose co-transporter 2 (SGLT2) in the eyes. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for predicting enavogliflozin exposures in the retina and to determine starting doses in first-in-human clinical trials of the ophthalmic enavogliflozin. Pharmacokinetic (PK) profiles for enavogliflozin in eleven tissues, including four eye segments, were obtained in rats to evaluate tissue distribution and estimate tissue-to-plasma partition coefficients. The rat PBPK model was established by the partition coefficients, physiological, and biochemical parameters, and validated using measured PK data in all tissues. Then, the human PBPK model was developed by substituting or extrapolating rat parameters with human ones for FIH dose selection. The estimated half-life (t 1/2 ) and time to reach peak concentration (T max ) of ophthalmic enavogliflozin ranged from 3.55 to 9.00 and 0.5–2.0 hr in all tissues except kidney (t 1/2 = ∼36 hr; T max = 8 hr) in rats. The order of tissue exposures after administration was: Kidney > Choroid > Cornea > GI tract > Vitreous humor > Plasma > Retina > Lung > Liver > Heart > Brain. Using the human model, the average retinal concentration of enavogliflozin was simulated and compared to the IC 50 value for SGLT2 inhibition. The optimized starting dose for once-daily dosing simulation was determined to range from 0.0092 to 0.0293 mg. These findings provide a scientific basis for further clinical studies of ophthalmic enavogliflozin as a noninvasive therapeutic formulation for diabetic retinopathy.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2025.118722

Authors: Dong Wook Kang, Seok-jin Cho, Go-Wun Choi, Ju Hee Kim, Hea-Young Cho

Institution: CHA University

Language: English

Topic: Pharmaceutical studies and practices

Subfield: Pediatrics, Perinatology and Child Health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,610