title: Levofloxacin-Induced QTc Prolongation Depends on the Time of Drug Administration.
abstract: Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug-induced QTc prolongation, a randomized, crossover, clinical trial was conducted in which 12 healthy male subjects received levofloxacin at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00. Using a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to account for variations in PKs, heart rate, and daily variation in baseline QT, we find that the concentration-QT relationship shows a 24-hour sinusoidal rhythm. Simulations show that the extent of levofloxacin-induced QT prolongation depends on dosing time, with the largest effect at 14:00 (1.73 (95% prediction interval: 1.56-1.90) ms per mg/L) and the smallest effect at 06:00 (-0.04 (-0.19 to 0.12) ms per mg/L). These results suggest that a 24-hour variation in the concentration-QT relationship could be a potentially confounding factor in the assessment of drug-induced QTc prolongation.
authors.affiliation: Laboratory for Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.|Centre for Human Drug Research, Leiden, The Netherlands.|Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Kervezee
authors.affiliation: Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Gotta
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Birkhoff
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Imc
authors.initials: I
authors.lastname: Kamerling
authors.affiliation: Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Laboratory for Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Meijer
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands. kb@chdr.nl.|Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands. kb@chdr.nl.
authors.forename: J
authors.initials: J
authors.lastname: Burggraaf
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002940:Circadian Rhythm / Q000187:drug effects* / Q000502:physiology; D002986:Clinical Trials as Topic / Q000379:methods; D003198:Computer Simulation; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D064704:Levofloxacin / Q000008:administration & dosage* / Q000097:blood; D008133:Long QT Syndrome / Q000097:blood / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D011897:Random Allocation; D055815:Young Adult
chemical_list: D064704:Levofloxacin