Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Luseogliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus

Abstract

Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that reduces hyperglycemia in type 2 diabetes mellitus (T2DM) by promoting urinary glucose excretion (UGE). A clinical pharmacology study conducted in Japanese patients with T2DM confirmed dose-dependency of UGE with once-daily administration of luseogliflozin; however, the reason for sustained UGE after plasma luseogliflozin decreased was unclear. To elucidate the effect of inhibition rate constants, K on and K off , and to explain the sustained UGE, a pharmacokinetic-pharmacodynamic (PK-PD) model was built based on the mechanisms of glucose filtration in the glomerulus and reabsorption in the renal proximal tubule of kidney as well as the kinetics of competitive inhibition of SGLT1/2 and inhibition rate constants of SGLT2, by using UGE and plasma glucose levels and luseogliflozin concentrations. This acquired population PK-PD model adequately described the sustained UGE and the estimated population means of the inhibition constant for SGLT2 (K i2 ) and inhibition-rate constants for SGLT2 (K on and K off ) were 0.31-and 3.6-fold lower or higher than the in vitro values. Because the dissociation half-time of luseogliflozin from SGLT2 calculated from K off , 6.81 h, was consistent with the value in vitro, we considered that the sustained UGE could be explained by the long dissociation half-time. Moreover, by calculating the SGLT2 inhibition ratio using the model, we discuss other properties of the UGE time course after luseogliflozin administration.Key words luseogliflozin; urinary glucose excretion; pharmacokinetic-pharmacodynamic model; sodium glucose co-transporter 2; type 2 diabetes mellitus In the human kidney, plasma glucose entering the glomeruli is filtered into the nephron fluid, and the filtered glucose is reabsorbed almost completely by two isoforms of sodium glucose co-transporter (SGLT), SGLT2 and SGLT1. SGLT2 is a high-capacity, low-affinity glucose transporter located in the early convoluted segment (S1 segment) of the proximal tubule that mediates 90% of renal glucose reabsorption. SGLT1 is a high-affinity, low-capacity glucose transporter located in the straight section of the proximal tubule (S3 segment) that is responsible for 10% of renal glucose reabsorption. 1) Inhibition of SGLT2 causes glucose excretion in urine and a reduction in plasma glucose. Several SGLT2 inhibitors have been developed for treatment of type 2 diabetes mellitus (T2DM). 2-4)Luseogliflozin is a novel selective SGLT2 inhibitor 5,6) currently marketed for the treatment of T2DM. The recommended dose is 2.5 mg (or 5 mg depending on the symptoms) once daily before or after breakfast. Studies in Japanese patients with T2DM have confirmed that treatment with luseogliflozin increases urinary glucose excretion (UGE) and reduces plasma glucose levels. [7][8][9][10][11][12] In a clinical pharmacology study conducted in Japanese patients with T2DM, reported by Sasaki et al., intensive sampling of UGE (nine sampling intervals a day) was performed and UGE ...

Pharmacokinetics and pharmacodynamics of rongliflozin, a novel selective inhibitor of sodium‐glucose co‐transporter‐2, in people with type 2 diabetes mellitus

“…However, at the same dose, when serum glucose was slightly higher in women than men, UGE was lower in women than men; when serum glucose was slightly lower in women than men, UGE was obviously lower in women than men. Considering the mechanism of SGLT2 inhibitors, we speculate that the response to rongliflozin was less potent in women compared with men . The glucose‐lowering effect of SGLT2 inhibitors is accompanied by the loss of calories and circulation fluid through the urine, potentially resulting in weight loss, as well as decreases in lipid levels and blood pressure.…”

“…Considering the mechanism of SGLT2 inhibitors, we speculate that the response to rongliflozin was less potent in women compared with men. 32,33 The glucose-lowering effect of SGLT2 inhibitors is accompanied by the loss of calories and circulation fluid through the urine, potentially resulting in weight loss, as well as decreases in lipid levels and blood pressure. Because the duration of treatment in these studies was relatively short, it was not possible to investigate such issues in depth.…”

Using a Mathematical Modeling To Simulate Pharmacokinetics and Urinary Glucose Excretion of Luseogliflozin and Explore the Role of SGLT1/2 in Renal Glucose Reabsorption

“…Several mathematical models for UGE have been published, including the UGE model in rat/mice, , UGE combined PK/PD model, , and system pharmacology model in humans. ,, Although this PBPK-UGE model has some advantages, we have also recognized that there are still some limitations to the present model. The biggest limitation is that it cannot simulate the dynamic change in the plasma glucose level induced by the combined result of glucose intake from food and regulation of glucose metabolism by insulin and UGE with LUS treatment.…”

Basic and Clinical Pharmaco-Therapeutics of SGLT2 Inhibitors: A Contemporary Update

“…Various available SGLT2 inhibitors, and their basic pharmacological characteristics, are summarized in Table 7 [66,67,[71][72][73][74][75][76][77][78][79][80][81][82].…”