Evaluation of the effect of dapagliflozin on cardiac repolarization: a thorough QT/QTc study

نویسندگان

  • Glenn F. Carlson
  • Conrad K. P. Tou
  • Shamik Parikh
  • Bruce K. Birmingham
  • Kathleen Butler
چکیده

INTRODUCTION Dapagliflozin is a first-in-class sodium-glucose transporter 2 (SGLT2) inhibitor under investigation for the treatment of type 2 diabetes mellitus. A thorough QTc study was conducted, according to International Conference on Harmonization E14 guidelines, to characterize the effect of dapagliflozin on cardiac repolarization. METHODS The present study was a double-blind, four-period, placebo-controlled crossover study at a single-center inpatient clinical pharmacology unit. The study enrolled 50 healthy men who were randomized to receive sequences of single doses of dapagliflozin 150 mg, dapagliflozin 20 mg, moxifloxacin 400 mg, and placebo. The sequences were randomized based on the Williams design for a cross-over study to reduce the "carryover" effects from drug-to-drug even with sufficient washout periods. Digital 12-lead electrocardiograms were recorded at nine time points over 24 hours in each period. QT intervals were corrected for heart rate using a study-specific correction factor (QTcX) and Fridericia's formula. RESULTS For dapagliflozin, the upper bound of the one-sided 95% confidence interval (CI) for time-matched, placebo-subtracted, baseline adjusted QTc intervals (ΔΔQTc) was <10 ms. ΔΔQTc was independent of dapagliflozin concentrations. No QTc thresholds >450 ms or QTc increases >30 ms were observed. Moxifloxacin increased the mean QTcX interval by 7.7 ms (lower bound 90% CI, 6.2 ms) over 1-4 hours after dosing, confirming assay sensitivity. CONCLUSION Dapagliflozin, at supratherapeutic doses, does not have a clinically significant effect on the QT interval in healthy subjects.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

The impact of chronic hemodialysis on QT dispersion corrected QTdispersion and maximum QT-dispersion

Introduction: Sudden cardiac death is common in patients on hemodialysis and may occur in the immediate postdialysis period when ventricular premature complexes are common. QT dispersion reflecting hetovogelity in ventricle repolarization has been used for predicting patients with risk of malignant arrhythmia and sudden death. The purpose of the study was to assess the effect of hemodialysis on...

متن کامل

Lack of effect of perampanel on QT interval duration: Results from a thorough QT analysis and pooled partial seizure Phase III clinical trials

INTRODUCTION Perampanel is a selective, noncompetitive AMPA receptor antagonist approved as adjunctive treatment for partial seizures. To assess potential for delayed cardiac repolarization, a Phase I thorough QT study was performed, supplemented by plasma concentration-QT data modeled from 3 pooled Phase III studies. METHODS The Phase I thorough QT study (double-blind, combined fixed-sequenc...

متن کامل

The Acute Effect of Passive Smoking on QT Dispersion in 95 Healthy Men

Background: Passive cigarette smoking is a known cause of a variety of diseases.  However, most of the studies done in this field have focused on its chronic effects on human health.  Studies considering the acute effect of smoking on QT dispersion, on the other hand, with its known predictive role in the occurrence ventricular arrhythmia and sudden cardiac death are sparse. Objectives: This st...

متن کامل

The Acute Effect of Cigarette Smoking on QT Dispersion

Background: Cigarette smoking has several known detrimental effect on cardiovascular system.  QT dispersion (QTd) is among the important predictors of cardiac death. Objective:  To assess the acute effect of smoking of a single standard cigarette on QT and QTc (corrected QT) dispersion, hence on the risk of ventricular arrhythmias in healthy smokers and non-smokers. Methods: 111 healthy men wit...

متن کامل

Supratherapeutic dose evaluation and effect of lesinurad on cardiac repolarization: a thorough QT/QTc study

INTRODUCTION Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and Europe for treatment of gout in combination with a xanthine oxidase inhibitor. A maximum tolerated dose study was conducted to determine the lesinurad supratherapeutic dose, followed by a thorough QTc study to characterize the effect of lesinurad on cardiac repolarization. METHODS The maxi...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:

دوره 2  شماره 

صفحات  -

تاریخ انتشار 2011