(T1330-02-08) First-in-Human Dose Optimization of Enavogliflozin Eye Drops via Population PBPK Modeling for Treatment of Diabetic Retinopathy

Purpose: Enavagliflozin is an orally administered sodium-glucose co-transporter 2 (SGLT2) inhibitor to treat type 2 diabetes mellitus (T2DM) patients. Recently, an ophthalmic solution of enavogliflozin was developed for the treatment of diabetic retinopathy in patients with T2DM. This study aimed to predict the pharmacokinetics of ophthalmic enavogliflozin in target tissues and assess its potential effects and tolerability using a population physiologically based pharmacokinetic (pop-PBPK) model. The pop-PBPK model offered a novel approach to determining the optimal dosing regimen for enavogliflozin as an ophthalmic formulation.

Methods: To investigate the pharmacokinetics and tissue distributions of opthalmic enavogliflozin, an animal study was conducted using Sprague Dawley rats (7 weeks, 306-344 g). A single topical dose of 5 μL 0.5% enavogliflozin ophthalmic solution (0.025 mg per eye) was administered to both eyes of each rat. To quantitate time-course drug concentration in major tissues (cornea, vitreous humor, retina, choroid, brain, lung, heart, gastrointestinal (GI) tract, liver, kidney, and plasma), each tissue was harvested by sacrificing the rats at the sampling time of 0.5, 1, 2, 4, 8, 12 and 24 hours after the drug administration. The enavogliflozin concentrations in the tissues were quantitated using UPLC-MS/MS. The pop-PBPK model was developed using Phoenix WinNonlin software, incorporating eight physiological compartments: blood, eyes, brain, lung, heart, gastrointestinal tract, liver, and kidney. The eye compartment was further divided into four segments: cornea, vitreous humor, retina, and choroid. (Figure 1) The input parameters for the pop-PBPK model consisted of tissue-to-plasma partition coefficients, physiological parameters, and biochemical parameters. The rat pop-PBPK model was first developed and validated, followed by extrapolating parameters into humans. The human pop-PBPK model was used for multiple-dosing simulations to predict drug effects and assess tolerability and safety in humans. The simulated enavogliflozin concentrations in the target tissues (retina and kidney) and the half-maximal inhibitory concentration (IC₅₀; 0.3575 μg/L) for SGLT-2 inhibition were compared to evaluate the potential efficacy of the ophthalmic formulation. In addition, the simulated blood concentrations of enavogliflozin were compared with the reported maximum tolerated concentrations (MTC) to assess the tolerability and safety of the ophthalmic formulation in humans. The simulation results determined the minimum effective dose (MED) and maximum tolerated dose (MTD), and the FIH dose range was optimized.

Results: The tissue t_1/2 was estimated to be less than 10 hours (3.55-9.00 hours) with the T_max between 0.5 and 2.0 hours except for the kidney. Enavogliflozin showed the longest t_1/2 of about 36 hours in the kidney and reached the T_max at 8 hours. After the single ophthalmic instillation of the enavogliflozin, the order of tissue exposures expressed as the AUC_last was as follows: Kidney > Choroid > Cornea > GI tract > Vitreous humor > Plasma > Retina > Lung > Liver > Heart > Brain. Using the simulation results from the pop-PBPK model, the relationship between ocular dose and tissue concentrations in the target tissues was predicted (Figure 2). The MEDs of the ophthalmic solution were determined to be 0.0469 mg for QD, 0.0245 mg for BID, and 0.0157 mg for TID. The MTDs of the ophthalmic formulation were determined to be 0.4216 mg for QD, 0.2164 mg for BID, and 0.1399 mg for TID. The corresponding concentrations at steady state for all dosage regimens did not exceed the reported MTCs, implying that the ophthalmic formulation of enavogliflozin might be well-tolerated at up to the above doses in humans. Also, the average tissue concentration of enavogliflozin after administering the MED of the ophthalmic formulation was predicted to exceed the reported IC₅₀ for SGLT-2 inhibition in the retina and kidney (Figure 3). This suggests that the enavogliflozin ophthalmic formulation may have potential efficacy not only for its target indication, diabetic retinopathy, but also for improving glycemic control and reducing renal complications. Therefore, the dosage regimens of 0.0469–0.4216 mg QD, 0.0245–0.2164 mg BID, and 0.0157–0.1399 mg TID were all considered efficacious and safe. Considering dosing convenience and patient adherence, QD administration starting at 0.0469 mg, followed by escalation to 0.4216 mg, was recommended for further evaluation in humans.

Conclusion: Using the pop-PBPK model, the FIH dosing strategies for the enavogliflozin eye drops were successfully designed. This comprehensive assessment of inter-individual variability, safety, and efficacy for optimizing clinical starting doses provides a scientific basis for initial clinical trials, supporting the druggability of enavogliflozin as a safe and non-invasive treatment for diabetic retinopathy.

References: [1] Cho et al., Multicompartmental pharmacokinetic evaluation of enavogliflozin eye drop formulation: Understanding its distribution to posterior segments, Journal of Pharmaceutical Investigation, 2024, 54, 329-343
[2] Hwang et al., Dose-dependent glucosuria of DWP16001, a novel selective sodium–glucose cotransporter-2 inhibitor, in healthy subjects, British Journal of Clinical Pharmacology, 2022, 88(9), 4100-4110
[3] Jeong et al., The effect of renal function on the pharmacokinetics and pharmacodynamics of enavogliflozin, a potent and selective sodium-glucose cotransporter-2 inhibitor, in type 2 diabetes, Diabetes, Obesity and Metabolism, 2024, 26(7), 2588-2597
[4] Kim et al., Physiologically Based Pharmacokinetic Modelling to Predict Pharmacokinetics of Enavogliflozin, a Sodium-Dependent Glucose Transporter 2 Inhibitor, in Humans, Pharmaceutics, 15(3), 942

Acknowledgements: The study was approved by the Institutional Animal Care and Use Committee (IACUC) of the Laboratory Animal Research Center at CHA University (approval No. IACUC220109).


Figure 1. The structure of the PBPK model for the ophthalmic formulation of enavogliflozin.


Figure 2. Model prediction and observations for tissue concentrations of enavogliflozin ophthalmic formulation. The open circles are measured concentrations, and the black solid lines are predicted concentrations. The gray solid lines represent the 2.5th-97.5th percentile range. The unit of the y-axis is tissue concentrations (μg/L).


Figure 3. Simulated PK profiles of enavogliflozin ophthalmic formulation at MED and MTD doses following (A) QD, (B) BID, and (C) TID administrations. The left and middle columns represent the retina and kidney concentrations of enavogliflozin after MED administration. The right column represents the blood concentrations of enavogliflozin after MTD administration. Black solid lines are the median simulated concentrations, and gray solid lines are the lower and upper limits of 90% CI for simulated concentrations. The blue dashed lines represent the MEC, and the red dashed lines represent the MTCs.