Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138.
This study investigates repolarization changes induced by a new candidate drug to determine whether a composite electrocardiographic (ECG) measure of T-wave morphology could be used as a reliable marker to support the evidence of abnormal repolarization, which is indicated by QT interval prolongation. Seventy-nine healthy subjects were included in this parallel study. After a baseline day during which no drug was given, 40 subjects received an I(Kr)-blocking antipsychotic compound (Lu 35-138) on 7 consecutive days while 39 subjects received placebo. Resting ECGs were recorded and used to determine a combined measure of repolarization morphology (morphology combination score [MCS]), based on asymmetry, flatness, and notching. Replicate measurements were used to determine reliable change and study power for both measures. Lu 35-138 increased the QTc interval with corresponding changes in T-wave morphology as determined by MCS. For subjects taking Lu 35-138, T-wave morphology was a more reliable indicator of I(Kr) inhibition than QTcF (chi(2) = 20.3, P = .001). At 80% study power for identifying a 5-millisecond placebo-adjusted change from baseline for QTcF, the corresponding study power for MCS was 93%. As a covariate to the assessment of QT interval liability, MCS offered important additive information to the effect of Lu 35-138 on cardiac repolarization.
Graff
Claus
C
Department of Health Science and Technology, Center for Sensory Motor Interaction, Aalborg University, Aalborg, Denmark. cgraff@hst.aau.dk
Matz
Jørgen
J
Christensen
Ellen B
EB
Andersen
Mads P
MP
Kanters
Jørgen K
JK
Toft
Egon
E
Pehrson
Steen
S
Hardahl
Thomas B
TB
Nielsen
Jimmi
J
Struijk
Johannes J
JJ
D000293:Adolescent; D000328:Adult; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors*; D004095:Dihydropyridines / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular
C527164:3-(1-(2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl)-3,6-dihydro-2H-pyridin-4-yl)-6-chloro-1H-indole; D051668:Delayed Rectifier Potassium Channels; D004095:Dihydropyridines; D007211:Indoles