Model-based Prediction of the Long-term Glucose-Lowering Effects of Ipragliflozin, a Selective Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor, in Patients with Type 2 Diabetes Mellitus.

Introduction: Sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors inhibit the reabsorption of glucose from the kidneys and increase urinary glucose excretion (UGE), thereby lowering the blood glucose concentration in people suffering from type 1 and type 2 diabetes mellitus (T2DM). In a previous study, we reported a pharmacokinetics/pharmacodynamics model to estimate individual change in UGE (ΔUGE), which is a direct pharmacological effect of SGLT2 inhibitors. In this study, we report our enhancement of the previous model to predict the long-term effects of ipragliflozin on clinical outcomes in patients with T2DM.

Pharmacokinetic and pharmacodynamic modelling for renal function dependent urinary glucose excretion effect of ipragliflozin, a selective sodium-glucose cotransporter 2 inhibitor, both in healthy subjects and patients with type 2 diabetes mellitus.

Aims: To provide a model-based prediction of individual urinary glucose excretion (UGE) effect of ipragliflozin, we constructed a pharmacokinetic/pharmacodynamic (PK/PD) model and a population PK model using pooled data of clinical studies.

Methods: A PK/PD model for the change from baseline in UGE for 24 hours (ΔUGE ) with area under the concentration-time curve from time of dosing to 24 h after administration (AUC ) of ipragliflozin was described by a maximum effect model. A population PK model was also constructed using rich PK sampling data obtained from 2 clinical pharmacology studies and sparse data from 4 late-phase studies by the NONMEM $PRIOR subroutine.

Improved cardiometabolic risk factors in Japanese patients with type 2 diabetes treated with ipragliflozin: a pooled analysis of six randomized, placebo-controlled trials.

To examine differential improvements among cardiovascular risk factors in response to treatment with ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients, we conducted a pooled analysis of six randomized, double-blind trials of Japanese T2DM patients who received ipragliflozin 50 mg/day or placebo and had patient-level data for cardiometabolic risk parameters. Risk factors included glycated hemoglobin (HbA1c), body weight, homeostatic model assessment for insulin resistance and beta-cell function (HOMA-R and HOMA-beta, respectively), systolic blood pressure, fasting serum insulin concentrations, and the concentration of uric acid, lipids, and liver enzymes from baseline to end of treatment (EOT; 12-24 weeks). The primary endpoint of each trial was the change in HbA1c from baseline to EOT.

Effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus: a pooled analysis of six randomized, placebo-controlled clinical trials.

Our aim was to examine the effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus (T2DM). We conducted a pooled analysis of double-blind trials of Japanese T2DM patients, randomized to 50 mg ipragliflozin or placebo, with patient-level data for the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline to end of treatment (12-24 weeks). Data from six trials were analyzed: ipragliflozin was administered as monotherapy in two; in combination with metformin, pioglitazone, or sulfonylurea in one each; and in combination with prior therapy in patients with renal impairment in one.

Efficacy and safety of ipragliflozin in Japanese patients with type 2 diabetes stratified by body mass index: A subgroup analysis of five randomized clinical trials.

Aims/introduction: The influence of overweight/obesity on the clinical efficacy and safety of sodium-glucose co-transporter 2 inhibitors is unclear. We carried out a pooled analysis to examine the impact of body mass index on the efficacy and safety of ipragliflozin.

Materials And Methods: Patient-level data were pooled for five Japanese double-blind trials (NCT00621868, NCT01057628, NCT01135433, NCT01225081 and NCT01242215) in which patients were randomized to ipragliflozin or a placebo as monotherapy, or in combination with metformin, pioglitazone or a sulfonylurea.

Randomized, placebo-controlled, double-blind glycemic control trial of novel sodium-dependent glucose cotransporter 2 inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus.

Aims/introduction: In the present dose-response study, we evaluated the efficacy and safety of ipragliflozin (ASP1941), a novel and selective inhibitor of sodium-dependent glucose cotransporter 2, in Japanese patients with type 2 diabetes mellitus.

Materials And Methods: A total of 361 patients from 39 Japanese centers were randomized to receive either once-daily oral ipragliflozin (12.5, 25, 50 or 100 mg) or a placebo for 12 weeks.

Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study.

Aims: Ipragliflozin is a novel and highly selective sodium-glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM.

Methods: In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50mg or 100mg ipragliflozin once daily for 14 days.

Synthesis and structure-activity relationships of a series of substituted 2-(1H-furo[2,3-g]indazol-1-yl)ethylamine derivatives as 5-HT2C receptor agonists.

A series of novel indazole derivatives were synthesized, and their structure-activity relationships examined in order to identify potent and selective 5-HT2C receptor agonists. Among these compounds, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348) had a good in vitro profile, that is, high agonistic activity to the human 5-HT2C receptor subtype (EC50 = 1.0 nM) and high selectivity over 5-HT2A receptors.

New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation.

The syntheses and biological evaluation of a series of novel indeno[1,2-d]thiazole derivatives are described. Several groups reported 5-HT(3) receptor agonists which were mainly evaluated for their activities on the von Bezold-Jarisch reflex (B-J reflex). We discovered that tetrahydrothiazolopyridine derivative 1b had a contractile effect on the isolated guinea pig colon with weak B-J reflex.