Eltrombopag does not affect cardiac repolarization: results from a definitive QTc study in healthy subjects.
BACKGROUND
Some non-anti-arrhythmic drugs delay cardiac repolarization, which can be measured as an increase in the QT interval. Delays in cardiac repolarization create an electrophysiological environment that favours the development of cardiac arrhythmias, which may lead to torsade de pointes, which can be fatal. As part of the clinical development of eltrombopag, a thorough QT(c) study was conducted to evaluate the effects of eltrombopag on cardiac repolarization at both therapeutic and supratherapeutic doses and to characterize the relationship between plasma eltrombopag concentrations and change in QT(c).


CONCLUSIONS
This study found no clinically significant QT prolongation for eltrombopag when administered as 50 mg or 150 mg every day for 5 days. There were no safety or tolerability signals of clinical concern. A small incidence of ventricular premature beats was observed, but this was consistent with previously reported incidences in healthy volunteers without apparent heart disease.


OBJECTIVE
To evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QT(c).


METHODS
This was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences.


RESULTS
Eighty-seven subjects entered the study and 48 completed. There was no prolongation of QT(c) (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QT(c)F between drug and placebo (ddQT(c)F) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag C(max) and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days' dosing. Proportions of subjects with adverse events were similar across treatments (52-66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug.


CONCLUSIONS
No clinically significant QT(c) prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses.
Matthys
Gemma
G
GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA. gemma.m.matthys@gsk.com
Park
Jung Wook
JW
McGuire
Sandra
S
Wire
Mary Beth
MB
Zhang
Jianping
J
Bowen
Carolyn
C
Williams
Daphne
D
Jenkins
Julian M
JM
Peng
Bin
B
D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000517:prevention & control; D001372:Aza Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D004812:Epidemiologic Methods; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome; D055815:Young Adult
D000890:Anti-Infective Agents; D001372:Aza Compounds; D001565:Benzoates; D024841:Fluoroquinolones; D006834:Hydrazines; D011720:Pyrazoles; D011804:Quinolines; C520809:eltrombopag; D000077266:Moxifloxacin