Eunsol Yang 1,2, Yoonjin Kim 1, Jaegu Kang 1, Seoyeon Yoon 3, Chan Ho Park 3, SeungHwan Lee 1
1 Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital (Seoul, Republic of Korea), 2 Department of Bioengineering and Therapeutic Sciences, University of California (San Francisco, San Francisco, United States of America ), 3 Daewoong Pharmaceutical (Seoul, Republic of Korea)
Objectives (167 words): Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antihyperglycemic agents for the treatment of type 2 diabetes (T2D) that lower plasma glucose levels by blocking renal glucose reabsorption and increasing urinary glucose excretion (UGE). Due to this mechanism, SGLT2 inhibitors exhibit a dose-dependent, saturable response inherently tied to kidney function, thereby generally limiting their clinical utility for patients with severe renal impairment. Enavogliflozin is a novel, selective SGLT2 inhibitor approved in the Republic of Korea for the treatment of T2D with 0.3 mg once-daily regimen. Although its pharmacokinetic (PK), UGE, and HbA1c changes have been investigated across multiple trials, the exposure-response relationship linking glucosuria to subsequent glycemic outcomes has not been comprehensively characterized. Furthermore, evidence regarding the impact of renal function on its glycemic efficacy remains limited. Here, we aimed to quantitatively characterize the exposure-response relationship of enavogliflozin for its glucosuric and HbA1c-lowering effects, provide model-informed evidence to support its use across varying renal function stages, and explore the potential influence of ethnicity on its exposure and response.
Methods (130 words): First, we integrated data from ten enavogliflozin clinical trials in Korean participants, comprising five Phase 1 studies in 203 healthy volunteers and five Phase 1/2/3 studies in 221 patients with T2D. We sequentially developed and linked population PK, population PK-pharmacodynamic (PD), and population PD-efficacy models. The developed models were used to simulate steady-state PK, PD, efficacy profiles following once-daily administration of 0.1 to 5 mg enavogliflozin for 221 trial patients with T2D, utilizing their individual-level baseline data. Finally, we incorporated data from an additional Phase 3 study in 151 Chinese patients with T2D and refitted the developed PK and PK-efficacy models by applying the same modeling approach used for the integrated analysis. Model development and simulation was performed using a nonlinear mixed-effect modeling approach with NONMEM v7.4.4 through PsN v5.3.0.
Results (271 words): The PK-PD-efficacy relationship of enavogliflozin was well described by sequentially linking exposure to glucosuria and subsequent HbA1c reduction. Enavogliflozin PK were best characterized by a three-compartment model with zero-order absorption and first-order elimination. The PD data were well described by a sigmoid maximum effect (Emax) model characterizing change in UGE over 24 hours from baseline (∆UGE24h) as a function of area under the concentration-time curve from 0 to 24 h post-dose (AUC0-24h), where the maximum reachable glucosuric effect was dependent on both fasting plasma glucose and renal function. The efficacy data were adequately captured by a model combining a linear disease progression component, accounting for natural glycemic deterioration, with a drug effect component. This drug effect linked ∆UGE24h to change in HbA1c from baseline (∆HbA1c) through an Emax relationship, where baseline HbA1c was negatively correlated with the maximum achievable glycemic reduction. At the approved 0.3 mg dose, median ∆UGE24h and ∆HbA1c at week 24 in patients with T2D were predicted to be 61.8 g and -0.79%, respectively. Compared to those with normal renal function, median ∆UGE24h at a 0.3 mg dose was predicted to decline by 22% and 39% in patients with mild and moderate renal impairment, respectively. The resulting ∆HbA1c at week 24 was predicted to be -0.75% and -0.63%, respectively, indicating a less-than-proportional reduction in efficacy relative to glucosuria according to renal function. No visual correlations were observed between ethnicity and PK parameters including apparent clearance. Marginal differences in efficacy parameters across ethnic groups were noted, likely confounded by the imbalances in treatment regimens.
Conclusions (74 words): We established the first integrated framework linking enavogliflozin dose, systemic exposure, glucosuria, and HbA1c dynamics, providing a quantitative rationale for its clinical use in patients with T2D. This model-informed evidence also supported the appropriate use of enavogliflozin across varying degrees of renal function and suggested no need for dose adjustment in Chinese patients. Our framework will offer a solid foundation to support the further development and clinical application of enavogliflozin in diverse patient populations.
Reference: PAGE 34 (2026) Abstr 12078 [www.page-meeting.org/?abstract=12078]
Poster: Drug/Disease Modelling - Endocrine