Thorough QT/QTc study of tocilizumab after single-dose administration at therapeutic and supratherapeutic doses in healthy subjects

Int J Clin Pharmacol Ther. 2011 Nov;49(11):648-55. doi: 10.5414/cp201549.

Abstract

Objectives: The study was intended to determine whether tocilizumab has a threshold pharmacologic effect on cardiac repolarization as detected by QT/QTc prolongation on 12-lead electrocardiograms (ECGs) in healthy subjects.

Methods: This was a multicenter, double-blind, placebo- and active-controlled, parallel group study. Healthy subjects received either an intravenous infusion of tocilizumab 10 mg/kg (n = 30) or 20 mg/kg (n = 31), oral moxifloxacin 400 mg (n = 31), or placebo (n = 29). Triplicate ECGs were obtained at predose, 2 h postdose on Day 1, and on Days 8, 15, and 29. Blood samples for pharmacokinetic analyses were collected at predose and up to 28 days postdose. Adverse events and laboratory safety tests were assessed throughout the study.

Results: Estimated mean study-specific, heart rate-corrected QT interval change from time-matched baseline versus placebo was negative at all time points (range -5.4 to -1.0 ms); the associated upper bound of the 1-sided 95% confidence limit was below threshold (10 ms). No clinically significant abnormalities in other electrocardiographic parameters were detected. No electrocardiographic abnormalities constituted an adverse event. After tocilizumab dosing, median time to maximum serum concentration was 2 h postdose; mean apparent terminal half-life was 9.3 ± 1.2 (10 mg/kg) and 12.1 ± 1.5 (20 mg/kg) days. Tocilizumab was well tolerated. Neutrophil counts decreased after tocilizumab administration, reaching a nadir 2 to 5 days after infusion. Mean neutrophil counts returned to baseline in the 10-mg/kg group and were near baseline in the 20-mg/kg group at the follow-up visit (Day 50 ± 2).

Conclusions: There was no QT prolongation effect of clinical concern by tocilizumab at both the therapeutic (10 mg/kg) and the supratherapeutic (20 mg/kg) dose in healthy subjects.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Double-Blind Method
  • Electrocardiography / drug effects*
  • Female
  • Humans
  • Male
  • Middle Aged

Substances

  • Antibodies, Monoclonal, Humanized
  • tocilizumab