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Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

Abstract：

PURPOSE:Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. METHODS:Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted. RESULTS:No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful. CONCLUSIONS:Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval. CLINICALTRIALS.GOV: NCT02271438.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

de Jong J,Hellemans P,Jiao JJ,Huang Y,Mesens S,Sukbuntherng J,Ouellet D

doi

10.1007/s00280-017-3471-x

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

1227-1237

issue

6

eissn

0344-5704

issn

1432-0843

pii

10.1007/s00280-017-3471-x

journal_volume

80

pub_type

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