Pharmacokinetics and Pharmacodynamics of the SGLT2 Inhibitor Remogliflozin Etabonate in Subjects with Mild and Moderate Renal Impairment

Abstract

Remogliflozin etabonate (RE), the prodrug of remogliflozin, is an inhibitor of the sodium glucose-dependent renal transporter 2 (SGLT2), enabling urinary glucose excretion to reduce hyperglycemia for the treatment of type 2 diabetes. Renal function declines more rapidly in patients with type 2 diabetes, making it difficult or unsafe to continue on some antidiabetic therapeutics. In an initial effort to understand the potential utility of RE in patients with renal impairment, the pharmacodynamics and pharmacokinetics of RE were evaluated in a single oral dose (250 mg) in patients with renal impairment as compared with control subjects. As shown by pharmacodynamic measurements of urinary glucose excretion, there was no clinically significant reduction in the ability of remogliflozin to inhibit SGLT2. In addition, there were no significant changes in area under the curve (from 0 to infinity) or half-life of remogliflozin, suggesting renal impairment does not alter the pharmacokinetics of remogliflozin. In contrast to other SGLT2 inhibitors which accumulate in patients with renal impairment, adjustment of the dosage of RE in subjects with mild or moderate renal impairment is not indicated based on the observations in this study.

Impact of Reduced Renal Function on the Glucose-Lowering Effects of Luseogliflozin, a Selective SGLT2 Inhibitor, Assessed by Continuous Glucose Monitoring in Japanese Patients with Type 2 Diabetes Mellitus

“…Several pharmacokinetic/pharmacodynamic studies have demonstrated that the effects of SGLT2 inhibitors on UGE and plasma glucose concentrations are attenuated by reduced renal function, especially severely reduced renal function or chronic kidney disease [ 6 , 15 – 18 ], consistent with our findings using 24-h CGM. Our results provide further insight into the impact of reduced renal function on the glucose-lowering effects of SGLT2 inhibitors, and that co-administration of a SGLT2 inhibitor with another antidiabetic drug, which improves postprandial glucose, might be useful for the patients with reduced renal function if improvements in glucose concentrations are not observed with monotherapy.…”

<p>Remogliflozin Etabonate in the Treatment of Type 2 Diabetes: Design, Development, and Place in Therapy</p>

“…After administration, RE is de-esterified by non-specific esterases present in mucosal cells of the gastrointestinal tract to get converted into its active form remogliflozin ( Figure 2B). 14 RE is rapidly and almost completely absorbed and available in the plasma within 10 minutes with a Tmax of 0.5-1 hour. 6 The administration with standard breakfast slightly delayed the Tmax by approximately 0.5-1.5 hours (hrs); however, there was no significant difference in the Cmax or Area under Curve (AUC) relative to the fasting state.…”

“…Metabolic products of RE are eliminated from the body through renal excretion. 14 In radiolabelled absorption, metabolic, and excretion (AME) studies, approximately 93% was excreted in the urine, of which about 11% of the dose was recovered as remogliflozin in urine; the majority of drug-related material is eliminated via the urine as inactive glucuronide metabolites. 14 The inhibitory concentration of remogliflozin was evaluated, and Ki values of 12.4 and 4520 nmol/l for SGLT2 and SGLT1, respectively, were demonstrated.…”

“…37,38 Study in Renal Impairment. This study was an open-label, single-dose, and parallel-group study, conducted by O'Connor-Semmes et al 14 that evaluated the effect of mild (estimated creatinine clearance (CLcr) of 50 to 80 mL/min) and moderate (estimated CLcr of 30 to 50 mL/min) renal impairment on PK and PD of RE. The mean renal clearance (CLr) of remogliflozin and GSK279782 was reduced by about 40% to 50% or 65% to 75% in subjects with mild to moderate renal impairment, respectively, and were highly correlated with CLcr.…”

Natural products with SGLT2 inhibitory activity: Possibilities of application for the treatment of diabetes

“…Additionally, mild to moderate renal impairment does not alter the pharmacokinetics and pharmacodynamics of RE, suggesting no dose adjustment of RE is necessary. This is an advantage of RE when compared with other SGLT2 inhibitors, including canagliflozin, dapagliflozin, and empagliflozin, where drug plasma accumulation has been shown in patients with mild to moderate renal impairment (O'Connor‐Semmes et al, ).…”