(1<i>S</i>)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-<scp>d</scp>-glucitol (TS-071) is a Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type 2 Diabetes Treatment

Kakinuma, Hiroyuki; Oi, Takahiro; Hashimoto-Tsuchiya, Yuko; Arai, Masayuki; Kawakita, Yasunori; Fukasawa, Yoshiki; Iida, Ikuo; Hagima, Naoko; Takeuchi, Hiroyuki; Chino, Yukihiro; Asami, Jun; Okumura-Kitajima, Lisa; Io, Fusayo; Yamamoto, Daisuke; Miyata, Noriyuki; Takahashi, Teisuke; Uchida, Seiichi; Yamamoto, Kōji

doi:10.1021/jm901893x

Cited by 142 publications

(113 citation statements)

References 44 publications

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“…Preclinical studies have shown that luseogliflozin is a specific and selective SGLT2 inhibitor 15 and that luseogliflozin improved glucose tolerance and reduced hyperglycemia in animal models of diabetes 16 . In a phase I study of luseogliflozin in healthy individuals 17 and a clinical pharmacology study that assessed the pharmacokinetic and pharmacodynamic profiles of luseogliflozin in patients with T2DM 18 , luseogliflozin dose dependently increased urinary glucose excretion without causing hypoglycemia.…”

Section: Including Luseogliflozin [Ts-071; (1s)-15-anhydro-1-[5-(4mentioning

confidence: 99%

Dose-finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, double-blind, placebo-controlled, phase II study

Seino

Sasaki

Fukatsu

et al. 2014

Current Medical Research and Opinion

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Section: Including Luseogliflozin [Ts-071; (1s)-15-anhydro-1-[5-(4mentioning

confidence: 99%

Dose-finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, double-blind, placebo-controlled, phase II study

Seino

Sasaki

Fukatsu

et al. 2014

Current Medical Research and Opinion

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“…Because SGLT2 inhibitors have an insulin-independent mechanism of action, these are expected to improve glycemic control with a low risk of major hypoglycemic events 11 . Luseogliflozin -a novel, orally bioavailable, 1-thio-D-glucitol derivative and a highly selective inhibitor of SGLT2 9,12 -lowered glucose levels by promoting urinary glucose excretion in animal models 12 . Results from the previous 12-week exploratory and dose-finding (phases 2a and 2b, respectively) clinical studies have shown that once daily administration of luseogliflozin leads to significant improvements in HbA1c as well as other glycemic parameters.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study

Seino

Sasaki

Fukatsu

et al. 2014

Current Medical Research and Opinion

124

123

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Objective: Luseogliflozin -a novel, orally bioavailable, 1-thio-D-glucitol derivative and a selective sodium glucose cotransporter 2 inhibitor -has shown efficacy and tolerability in previous phase 2 studies. This phase 3, randomized, double-blind, placebo-controlled, comparative study aimed to confirm the superiority of 24 week luseogliflozin 2.5 mg monotherapy over placebo in reducing hemoglobin A1c (HbA1c) levels in Japanese patients with type 2 diabetes mellitus (T2DM). Methods:Patients with HbA1c levels of 6.9%-10.5% were randomized to receive luseogliflozin 2.5 mg or placebo once daily for 24 weeks (n ¼ 79 in each group). The primary endpoint was change from baseline in HbA1c at end of treatment. Secondary endpoints included change from baseline in fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) following a meal tolerance test, body weight, and abdominal circumference. Safety assessments included adverse events (AEs), clinical laboratory tests, and vital signs.

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“…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.…”

Section: -4)mentioning

confidence: 99%

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

Samukawa

Mutoh

Chen

et al. 2017

Biological & Pharmaceutical Bulletin

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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 ...

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(1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol (TS-071) is a Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type 2 Diabetes Treatment

Cited by 142 publications

References 44 publications

Dose-finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, double-blind, placebo-controlled, phase II study

Dose-finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, double-blind, placebo-controlled, phase II study

Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study

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

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