Dabigatran Does Not Prolong the QT Interval with Supratherapeutic Exposure: a Thorough QT Study in Healthy Subjects

Abstract

BackgroundDabigatran etexilate is a pro-drug of the oral reversible direct thrombin inhibitor dabigatran that interacts with the active site in the catalytic domain of the thrombin molecule.ObjectiveTo assess the electrophysiological effects of therapeutic and supratherapeutic doses of dabigatran etexilate in healthy subjects, a thorough QT study was performed.MethodsIn this single-centre, blinded, placebo- and active-controlled, four-period, crossover study, 40 healthy Caucasian subjects (20 women and 20 men) received single oral doses of dabigatran etexilate (150 mg and 600 mg), moxifloxacin 400 mg (positive control) or placebo, in a randomized order. Electrocardiogram (ECG) profiles were recorded at baseline and during the randomized study treatment in each period. The individually heart-rate–corrected QT interval (QTcI) was the primary parameter. The primary endpoint was the mean of these QTcI values obtained at 1.5, 2 and 3 h following study drug administration minus the mean of the time-matched QTcI values obtained at baseline day −1. The hypothesis tested was that the difference between each of the two doses of dabigatran etexilate (150 mg and 600 mg) and placebo, for the mean time-matched change from baseline (CfB) of QTcI between 1.5 and 3 h (the primary endpoint), was greater than or equal to 10 ms. Secondary endpoints were the time-matched CfB of QTcI between 0.5 and 24 h post-dose.ResultsAll subjects completed the study without premature discontinuation and all treatments were well tolerated. Following dabigatran etexilate administration, the mean values of the placebo-adjusted time-matched CfB of QTcI between 1.5 and 3 h post-dose were close to 0; the upper bound of the two-sided 90 % confidence interval (CI) was 1.4 ms for dabigatran etexilate 150 mg and 1.3 ms for dabigatran etexilate 600 mg. The placebo-adjusted time-matched CfB of QTcI remained close to 0 at all time points, and all 90 % CIs were between −5 ms and 5 ms, well below the pre-defined non-inferiority margin of 10 ms.ConclusionThis thorough QT study demonstrated that therapeutic and fourfold supratherapeutic doses of dabigatran etexilate do not prolong QT intervals.

Drug–Drug Interactions of 257 Antineoplastic and Supportive Care Agents With 7 Anticoagulants: A Comprehensive Review of Interactions and Mechanisms

“…Drug-drug interaction of anticoagulants with antineoplastic and supportive care drugs resulting in increasing or decreasing levels of cancer drugs is not clinically significant, since DOACs, fondaparinux, and enoxaparin do not induce or inhibit cytochrome P450 or P-glycoprotein. Furthermore, neither anticoagulants are associated with QTc [29][30][31][32] interval prolongation, nor does it potentiate the effect of drugs that cause it, such as some tyrosine kinase inhibitors. Of great concern to oncologists and their patients are the DDI of anticoagulants with antineoplastic and supportive care drugs that result in modification of the effect of anticancer drugs, particularly tyrosine kinase inhibitors, due to serious adverse events.…”

Top-down, Bottom-up and Middle-out Strategies for Drug Cardiac Safety Assessment via Modeling and Simulations

“…Mixed model ANOVA applied by Morganroth [ 19 ] in crossover TQT study on betrixaban also included period, sequence, gender, and treatment-gender interaction as fixed terms. Mixed effects ANCOVA was used to analyze the time-matched change in QTc in crossover trials on retosiban [ 20 ], lenvatinib [ 21 ], umeclidinium and umeclidinium/vilanterol [ 22 ], dabigatran [ 23 ], and parallel trials on tafenoquine [ 24 ], and parallel group/crossover study on prucalopride [ 25 ]. Revised ANCOVA model besides random and fixed terms, accounted for baseline QTc as a covariate.…”