PII-015 - PHARMACOKINETICS AND PHARMACODYNAMICS OF ENAVOGLIFLOZIN, AN SGLT-2 INHIBITOR, IN TYPE 2 DIABETES PATIENTS WITH IMPAIRED RENAL FUNCTION.

Y. Kim¹, K. Huh¹, S. Jeong², J. Cho³, W. Huh³, Y. Shin⁴, J. Chung¹; ¹Seoul National University Bundang Hospital, Seoul, Republic of Korea, ²Chungbuk National University Hospital, Cheong-ju, Republic of Korea, ³Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea, ⁴iN Therapeutics, Yonginsi, Republic of Korea.

Background: As the glucosuric effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors depends on renal function, this study aimed to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of enavogliflozin, a SGLT2 inhibitor, in type 2 diabetes mellitus (T2DM) patients with impaired renal function.

Methods: An open-labeled, 2-part, clinical study was conducted in T2DM patients in the following groups: G1, normal renal function, G2/G3/G4, mild/moderate/severe renal impairment. In Part A, G1 and G3 received enavogliflozin 0.5 mg once daily for 7 days. In Part B, G2 and G4 received enavogliflozin 0.5 mg once. Serial blood and timed urine samples were collected to analyze the PK and PD of enavogliflozin. Pearson’s correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL) from 24h urine collection.

Results: A total of 21 subjects (6, 7, 3, and 5 subjects in G1-G4, respectively) completed the study. The area under the curve (AUC) of enavogliflozin was not significantly correlated with CrCL although the maximum concentration decreased as renal function decreased. In contrast, the daily urine glucose excretion (UGE0-24) was positively correlated with CrCL after both single (r = 0.7866, p < 0.0001) and multiple administration (r = 0.6606, p = 0.0438).

Conclusion: The systemic exposure to enavogliflozin was similar among the T2DM patients regardless of their renal functions. After multiple administrations, UGE0-24 is reported to decrease to 26 % - 77 %, compared to normal renal function patients in other SGLT2 inhibitors[1] and to a level of 61% in enavogliflozin. Although the glucosuric effect of enavogliflozin decreased as the patient’s renal function decreased, a clinically meaningful PD effect was preserved in T2DM patients with moderate renal impairment.

[1] Scheen AJ. Pharmacokinetic/Pharmacodynamic Properties and Clinical Use of SGLT2 Inhibitors in Non-Asian and Asian Patients with Type 2 Diabetes and Chronic Kidney Disease. Clin Pharmacokinet. 59(8):981-994 (2020).