title: A thorough QT study to assess the effects of tbo-filgrastim on cardiac repolarization in healthy subjects.
abstract: Tbo-filgrastim is a recombinant human granulocyte colony-stimulating factor approved by the US Food and Drug Administration to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. We assessed the effect of tbo-filgrastim on cardiac conduction and repolarization in healthy subjects. A three-arm, parallel-group, active- and placebo-controlled, double-blind study randomized healthy adults to a single 5 μg/kg intravenous tbo-filgrastim infusion, a single intravenous placebo infusion, or a single 400 mg moxifloxacin oral dose. The primary end point was placebo-corrected time-matched change from baseline in QT interval corrected using a QT individual correction (QTcI) method. Secondary end points included heart rate, PR interval, QRS duration, change in electrocardiogram patterns, correlation between QTcI change from baseline (milliseconds) and tbo-filgrastim serum concentrations, and safety variables. A total of 145 subjects were enrolled (50 tbo-filgrastim, 50 placebo, 45 moxifloxacin). Peak placebo-corrected change from baseline for QTcI with tbo-filgrastim was 3.5 milliseconds, with a two-sided 95% upper confidence interval of 7.2 milliseconds, demonstrating no signal for any tbo-filgrastim effect on QTc. Concentration-effect modeling showed no evidence of an effect of tbo-filgrastim on cardiac repolarization. Tbo-filgrastim produced no clinically significant changes in other electrocardiogram parameters. Tbo-filgrastim was well tolerated.
authors.affiliation: R&D, Teva Pharmaceutical Industries Ltd, Netanya, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Adar
authors.affiliation: R&D, Teva Pharmaceutical Industries Ltd, Netanya, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Avisar
authors.affiliation: Biosimilars Clinical Development, CPP Teva ratiopharm, Merckle GmbH, Ulm, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lammerich
authors.affiliation: Global Cardiology, eResearch Technology Inc, Philadelphia, PA, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Kleiman
authors.affiliation: R&D, Teva Pharmaceutical Industries Ltd, Netanya, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Spiegelstein
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D000069585:Filgrastim / Q000009:adverse effects*; D024841:Fluoroquinolones / Q000009:adverse effects; D006339:Heart Rate / Q000187:drug effects; D006401:Hematologic Agents / Q000009:adverse effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D000077266:Moxifloxacin; D055815:Young Adult
chemical_list: D024841:Fluoroquinolones; D006401:Hematologic Agents; D000069585:Filgrastim; D000077266:Moxifloxacin
keywords: QT interval; electrocardiogram; granulocyte colony-stimulating factor; tbo-filgrastim