TY - JOUR
T1 - Absence of effect of telbivudine on cardiac repolarization
T2 - Results of a thorough QT/QTc study in healthy participants
AU - Poordad, Fred
AU - Zeldin, Gillian
AU - Harris, Stuart I.
AU - Ke, June
AU - Xu, Limin
AU - Mayers, Douglas
AU - Zhou, Xiao Jian
PY - 2009/12
Y1 - 2009/12
N2 - 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 Fridericias 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.
AB - 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 Fridericias 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.
KW - Cardiac repolarization
KW - Pharmacodynamics
KW - Pharmacokinetics
KW - QT/QTc interval
KW - Telbivudine
UR - http://www.scopus.com/inward/record.url?scp=71449093977&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=71449093977&partnerID=8YFLogxK
U2 - 10.1177/0091270009337943
DO - 10.1177/0091270009337943
M3 - Article
C2 - 19833860
AN - SCOPUS:71449093977
SN - 0091-2700
VL - 49
SP - 1436
EP - 1446
JO - Journal of Clinical Pharmacology
JF - Journal of Clinical Pharmacology
IS - 12
ER -