title: Absence of effect of telbivudine on cardiac repolarization: results of a thorough QT/QTc study in healthy participants.
abstract: The effect of telbivudine on cardiac repolarization was evaluated in healthy participants at clinical and supratherapeutic doses. Sixty-two participants were enrolled, stratified by sex, and randomized according to a crossover design among 4 treatment sequences: placebo, a single moxifloxacin 400-mg dose as positive calibrator, and telbivudine 600 and 1800 mg/d for 7 days. Intensive time-matched electrocardiogram measurements and pharmacokinetic sampling were performed at baseline and on day 7 over 24 hours. For telbivudine and moxifloxacin, time-matched, placebo-adjusted change from baseline in QT was calculated and corrected using Fridericia's formula (QTcF). While moxifloxacin produced the expected significant changes in QTcF, none of the changes in QTcF for either doses of telbivudine exceeded 5 ms, and none of the associated upper 1-sided 95% confidence intervals (CI) exceeded the limit of 10 ms. There was no increase in QTcF with increasing plasma telbivudine. The supratherapeutic dose of telbivudine was well tolerated with a safety profile similar to the clinical dose despite a 3-fold increase in plasma exposure. This study therefore met the criteria for a negative thorough QT study. Telbivudine had no adverse effect on cardiac repolarization in healthy participants, even at supratherapeutic exposure, suggesting a broad safety margin.
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Poordad
authors.forename: Gillian
authors.initials: G
authors.lastname: Zeldin
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Harris
authors.forename: June
authors.initials: J
authors.lastname: Ke
authors.forename: Limin
authors.initials: L
authors.lastname: Xu
authors.forename: Douglas
authors.initials: D
authors.lastname: Mayers
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D015992:Body Mass Index; D018592:Cross-Over Studies; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006630:Hispanic or Latino; D006801:Humans; D008297:Male; D008875:Middle Aged; D009705:Nucleosides / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D012727:Sex Characteristics; D013223:Statistics as Topic; D000077712:Telbivudine; D013936:Thymidine / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D011744:Pyrimidinones; D000077712:Telbivudine; D013936:Thymidine