title: QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization.
abstract: The effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a phase I, randomized, double-blind study in healthy individuals who received isavuconazole (after 2-day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg q.d.), or placebo. A post-hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L-type Ca2+channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximum serum concentrations of nonprotein-bound isavuconazole in vivo. In the phase I study (n = 161), isavuconazole shortened the QT interval in a dose- and plasma concentration-related manner. There were no serious treatment-emergent adverse events; palpitations and tachycardia were observed in placebo and supratherapeutic isavuconazole groups; no cardiac safety signals were detected in the SECURE study (n = 257). Isavuconazole was associated with a shortened cardiac QT interval.
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, Illinois, USA.
authors.forename: J
authors.initials: J
authors.lastname: Keirns
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, Illinois, USA.
authors.forename: A
authors.initials: A
authors.lastname: Desai
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, Illinois, USA.
authors.forename: D
authors.initials: D
authors.lastname: Kowalski
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, Illinois, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lademacher
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, Illinois, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mujais
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, Illinois, USA.
authors.forename: B
authors.initials: B
authors.lastname: Parker
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, Illinois, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Schneidkraut
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, Illinois, USA.
authors.forename: R
authors.initials: R
authors.lastname: Townsend
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, Illinois, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wojtkowski
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, Illinois, USA.
authors.forename: T
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: PAREXEL, Glendale, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yen
authors.affiliation: Lankenau Medical Center and Institute for Medical Research, Main Line Health System, Wynnewood, Pennsylvania, USA.|Jefferson Medical College, Philadelphia, Pennsylvania, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Kowey
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000328:Adult; D000935:Antifungal Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008954:Models, Biological; D009570:Nitriles / Q000009:adverse effects* / Q000493:pharmacokinetics; D011725:Pyridines / Q000009:adverse effects* / Q000493:pharmacokinetics; D018570:Risk Assessment; D013997:Time Factors; D014162:Transfection; D014230:Triazoles / Q000009:adverse effects* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; C079146:CACNA1C protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole