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Clinical pharmacology study of ipragliflozin in Japanese patients with type 1 diabetes mellitus: A phase 2, randomized, placebo-controlled trial.

ABSTRACT: AIM:To evaluate the pharmacodynamics, pharmacokinetics, and safety of the novel oral sodium-glucose co-transporter-2 inhibitor, ipragliflozin, in Japanese patients with type 1 diabetes mellitus. MATERIALS AND METHODS:We conducted a multicentre, double-blind, placebo-controlled, parallel-group study. Patients were randomized to receive 25, 50, or 100?mg/day ipragliflozin or placebo for 2 weeks. Key pharmacokinetic endpoints included area under the concentration-time curve 24?hours postdose (AUC24h ), maximum plasma concentration (Cmax ), and renal clearance. Key pharmacodynamic endpoints included 24-hour urinary glucose excretion, mean plasma glucose AUC0-24h , and mean renal glucose clearance. Changes in total, basal, and bolus insulin dosages were recorded. Adverse events (AEs) were monitored for safety. RESULTS:Dose-dependent increases were observed in AUC24h and Cmax on days 1 and 14 for 25-, 50-, and 100-mg ipragliflozin. The mean plasma glucose AUC0-24h was lower than that of placebo and the mean renal glucose clearance increased in a dose-dependent manner from baseline, but remained unchanged in the placebo group. The mean (standard deviation) change from baseline in total daily insulin dose was greater in the ipragliflozin 25-, 50-, and 100-mg groups (-14.77?±?14.04%, -18.40?±?12.49% and?-19.25?±?16.77%, respectively), than placebo (-4.51?±?16.28%). Most AEs were mild in severity; no patients discontinued the study because of treatment-emergent AEs. CONCLUSIONS:The pharmacokinetic and pharmacodynamic properties of ipragliflozin in Japanese patients with type 1 diabetes mellitus were confirmed. Increases in urinary glucose excretion lead to dose-dependent decreases in plasma glucose. Concomitant insulin dose decreased with ipragliflozin treatment. No clinically relevant safety concerns were identified.

SUBMITTER: Kaku K

PROVIDER: S-EPMC6594083 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Clinical pharmacology study of ipragliflozin in Japanese patients with type 1 diabetes mellitus: A phase 2, randomized, placebo-controlled trial.

Kaku Kohei K Isaka Hiroyuki H Toyoshima Junko J Sakatani Taishi T

Diabetes, obesity & metabolism 20190408 6

<h4>Aim</h4>To evaluate the pharmacodynamics, pharmacokinetics, and safety of the novel oral sodium-glucose co-transporter-2 inhibitor, ipragliflozin, in Japanese patients with type 1 diabetes mellitus.<h4>Materials and methods</h4>We conducted a multicentre, double-blind, placebo-controlled, parallel-group study. Patients were randomized to receive 25, 50, or 100 mg/day ipragliflozin or placebo for 2 weeks. Key pharmacokinetic endpoints included area under the concentration-time curve 24 hours ...[more]

PMID: 30821047

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Project description:IntroductionLuseogliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, promotes urinary glucose excretion (UGE) and reduces plasma glucose concentrations. Luseogliflozin was approved for use in Japan after favorable pharmacokinetic, pharmacodynamic, and safety profiles were reported in healthy Japanese subjects and patients with type 2 diabetes mellitus (T2DM) in clinical development studies. We aimed to investigate the pharmacokinetics, pharmacodynamics, and safety of multiple doses of luseogliflozin administered once daily for 7 days in Japanese patients with T2DM.MethodsWe conducted a randomized, placebo-controlled, single-blind, parallel-group, clinical pharmacology study at the P-One Clinic, Keikokai Medical Corporation (Tokyo, Japan) between August 2009 and November 2009. Forty Japanese patients with T2DM were randomly assigned to receive once-daily 0.5, 1, 2.5 or 5 mg luseogliflozin or placebo for 7 days. We assessed the pharmacokinetics, pharmacodynamics (including changes in UGE and plasma glucose concentrations), and safety of luseogliflozin.ResultsThe plasma concentrations of luseogliflozin and its active metabolite, M2, were dose proportional, without accumulation. 24-h UGE was greater in all luseogliflozin groups versus placebo. Least-squares mean differences in 24-h UGE on Day 7 increased dose dependently in the luseogliflozin groups, with values of 49.2, 66.5, 89.4, and 101 g/day at 0.5, 1, 2.5, and 5 mg, respectively. On Day 7, the areas under the concentration-time curves for post-meal plasma glucose and the mean plasma glucose for 0-16 h were significantly lower in all luseogliflozin groups versus placebo. Seven patients had mild adverse events (AEs); all were resolved. No AEs led to study discontinuation.ConclusionOnce-daily administration of luseogliflozin for 7 days increased 24-h UGE in a dose-dependent manner, reduced plasma glucose concentrations, and was well tolerated in Japanese patients with T2DM. The pharmacokinetic and pharmacodynamic profile of luseogliflozin observed in this study supports its once-daily dosing regimen.FundingTaisho Pharmaceutical Co., Ltd.

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Clinical pharmacology study of ipragliflozin in Japanese patients with type 1 diabetes mellitus: A phase 2, randomized, placebo-controlled trial.

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Clinical pharmacology study of ipragliflozin in Japanese patients with type 1 diabetes mellitus: A phase 2, randomized, placebo-controlled trial.

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