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Pharmacokinetics and pharmacodynamics of dapagliflozin in combination with insulin in Japanese patients with type 1 diabetes.

ABSTRACT: AIMS:To assess the pharmacokinetics/pharmacodynamics (PK/PD) of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor that increases urinary glucose excretion (UGE) and its major metabolite, dapagliflozin-3-O-glucuronide (D3OG), in Japanese patients with type 1 diabetes (T1D) and inadequate glycaemic control (HbA1c 7%-10%). MATERIALS AND METHODS:Japanese patients (18-65?years) with inadequately controlled T1D were randomized 1:1:1 to dapagliflozin 5 mg, 10 mg or placebo (n?=?14 each) once daily for 7 days, with adjustable insulin. The PK/PD characteristics of dapagliflozin and D3OG were assessed on Day 7. Patients underwent follow-up evaluation on Days 8 and 14. Adverse events (AEs), hypoglycaemic episodes and events of diabetic ketoacidosis (DKA) were recorded over the treatment and follow-up periods. RESULTS:A total of 42 randomized patients received dapagliflozin or placebo. PK variables increased in a dose-dependent manner. D3OG was generated rapidly, with a median time to maximum plasma concentration of 2.0 hours (1.0-3.0). The dapagliflozin dose-UGE relationship was attenuated, with larger insulin dose reductions than anticipated. Mean percent (standard error) changes in total daily insulin dose from baseline to Day 7 were?-?36.86% (3.32), -39.13% (2.68) and?-?4.97% (5.28) for dapagliflozin 5 mg and 10 mg and for placebo, respectively. No DKA was reported. AEs were consistent with the established dapagliflozin safety profile. There was no increase in hypoglycaemia. CONCLUSIONS:The PK and safety profiles of dapagliflozin in Japanese patients with T1D were consistent with previous studies, but with an unanticipated attenuation of the PD dose-response measured as UGE.

SUBMITTER: Watada H

PROVIDER: S-EPMC6590304 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Pharmacokinetics and pharmacodynamics of dapagliflozin in combination with insulin in Japanese patients with type 1 diabetes.

Watada Hirotaka H Shiramoto Masanari M Ueda Shinya S Tang Weifeng W Asano Michiko M Thorén Fredrik F Kim Hyosung H Yajima Toshitaka T Boulton David W DW Araki Eiichi E

Diabetes, obesity & metabolism 20181221 4

<h4>Aims</h4>To assess the pharmacokinetics/pharmacodynamics (PK/PD) of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor that increases urinary glucose excretion (UGE) and its major metabolite, dapagliflozin-3-O-glucuronide (D3OG), in Japanese patients with type 1 diabetes (T1D) and inadequate glycaemic control (HbA1c 7%-10%).<h4>Materials and methods</h4>Japanese patients (18-65 years) with inadequately controlled T1D were randomized 1:1:1 to dapagliflozin 5 mg, 10 mg or placebo (n = ...[more]

PMID: 30499157

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Project description:IntroductionDapagliflozin is an orally administered selective sodium-glucose cotransporter 2 (SGLT2) inhibitor under development for the treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin lowers blood glucose through a reduction in renal glucose reabsorption. This study was performed to assess the effect of the oral antidiabetic agent voglibose [0.2 mg thrice daily (t.i.d.)] at steady-state, on the pharmacokinetics, safety and tolerability of dapagliflozin administered as a single oral dose (10 mg) to Japanese patients with T2DM.MethodsThis was an open-label, multi-center, drug-drug interaction study. A single oral dose of dapagliflozin (10 mg) was administered to 22 Japanese patients with T2DM in the presence and absence of voglibose (0.2 mg t.i.d.). Serial blood samples were collected before and at regular prespecified intervals after each dapagliflozin dose to determine dapagliflozin plasma concentrations and to evaluate pharmacokinetic parameters. Based on a mixed effect analysis of variance model, including the dosing condition as a fixed effect and patients as a random effect, the ratios of geometric means of area under curve from time 0 to infinity (AUC0-inf) and maximum observed plasma concentration (C max) with and without voglibose were estimated along with two-sided 90% confidence intervals (CIs).ResultsIn Japanese patients with T2DM, the exposure to dapagliflozin following a single oral dose of dapagliflozin 10 mg was not influenced by the concomitant administration of voglibose (0.2 mg t.i.d.). The geometric ratio (90% CI) for dapagliflozin AUC0-inf with/without voglibose was 1.009 (0.954, 1.067), and for C max 1.040 (0.899, 1.204). The median time to C max (t max) and plasma clearance of dapagliflozin were also similar between treatments. The mean half-life (t ½) for dapagliflozin was slightly higher when administered in combination with voglibose. Dapagliflozin 10 mg was well tolerated when administered alone and in combination with voglibose in Japanese patients with T2DM.ConclusionThe results presented here support the co-administration of dapagliflozin and voglibose without dose adjustment of either agent.

Project description:IntroductionCanagliflozin is a sodium glucose co-transporter 2 inhibitor approved worldwide for the treatment of patients with type 2 diabetes mellitus (T2DM). The present study evaluated pharmacokinetics, pharmacodynamics, and safety of canagliflozin in Japanese patients with T2DM.MethodsCanagliflozin, at doses of 25, 100, 200, or 400 mg, was administered as a single dose and, after a washout of 1 day, in repeated doses for 14 consecutive days to 61 subjects in a randomized, double-blind, placebo-controlled study. Plasma concentrations of canagliflozin and urinary glucose excretion (UGE) were measured, and renal threshold for glucose excretion (RTG) was calculated. Safety was evaluated on the basis of adverse event (AE) reports, blood and urine laboratory parameters, and vital signs.ResultsPlasma canagliflozin maximum concentration and area under the concentration-time curve (AUC) values increased in a dose-dependent manner with the time to maximum concentration (t max) of 1.0 h and elimination half-life (t 1/2) of 10.22-13.26 h on Day 1. No significant changes in t max and t 1/2 were observed after multiple-dose administration. The linearity factors, as calculated from the ratios of AUC0-24h on Day 16 to AUC0-∞ on Day 1, were close to 1 in all canagliflozin groups. Canagliflozin increased UGE0-24h (80-110 g/day with canagliflozin ≥100 mg) and decreased RTG from the first day of treatment; these effects were sustained during the entire period of multiple administration. No significant AEs were noted. Urine volume was slightly increased on Day 1, but subsequent changes after repeated doses for 14 days were small. Urinary sodium tended to be higher in the early treatment period, whereas no particular change was observed in serum osmolality and hematocrit.ConclusionCanagliflozin increased UGE, decreased RTG, and was well tolerated throughout the entire period of multiple administrations in Japanese patients with T2DM.FundingMitsubishi Tanabe Pharma Corporation.Trial registrationClinicalTrials.gov#NCT00707954.

Project description:INTRODUCTION:Dapagliflozin is a selective sodium glucose co-transporter 2 inhibitor that improves glycemic control and reduces body weight and systolic blood pressure in patients with type 2 diabetes mellitus (T2DM). Dapagliflozin is effective and well tolerated over 12-24 weeks in Japanese patients with T2DM. In this study, the safety and efficacy of dapagliflozin administered as monotherapy and combination therapy were assessed over 52 weeks in Japanese patients with T2DM. METHODS:This was a 52-week open-label Phase 3 study consisting of a single treatment arm with no comparator. Dapagliflozin was administered as monotherapy (n = 249) or combination therapy (n = 479) with existing antihyperglycemic agents (sulfonylurea, glinides, metformin, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, or glucagon-like peptide-1 receptor agonists) to Japanese patients with T2DM and inadequate glycemic control for 52 weeks. Treatment with dapagliflozin was initiated at 5 mg/day and titrated to 10 mg/day as required. RESULTS:Dapagliflozin administered as monotherapy or combination therapy was well tolerated. The frequency of adverse events (AEs) over 52 weeks was similar between monotherapy (79.1%) and combination therapy (72.4%) groups, and AEs were mostly mild or moderate. The incidence of hypoglycemia at 52 weeks was 2.4% in the monotherapy group and 4.0% in the combination therapy group. In patients receiving dapagliflozin as monotherapy or combination therapy, reductions from baseline to week 52 were observed in glycosylated hemoglobin (HbA1c) (-0.7% in both groups), weight (-2.6 and -2.1 kg, respectively), and systolic blood pressure (-5.2 mmHg and -3.9 mmHg). In patients with insufficient response to 5 mg/day, dapagliflozin was increased to 10 mg/day, and a further decrease in HbA1c from the pre-titration value was observed in both groups. CONCLUSION:Dapagliflozin was well tolerated and effective as monotherapy or combination therapy in Japanese patients with T2DM over 52 weeks.

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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Pharmacokinetics and pharmacodynamics of dapagliflozin in combination with insulin in Japanese patients with type 1 diabetes.

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Pharmacokinetics and pharmacodynamics of dapagliflozin in combination with insulin in Japanese patients with type 1 diabetes.

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