Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138

Claus Graff; Jørgen Matz; Ellen B Christensen; Mads P Andersen; Jørgen K Kanters; Egon Toft; Steen Pehrson; Thomas B Hardahl; Jimmi Nielsen; Johannes J Struijk

doi:10.1177/0091270009344853

Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138

Claus Graff, Jørgen Matz, Ellen B Christensen, Mads P Andersen, Jørgen K Kanters, Egon Toft, Steen Pehrson, Thomas B Hardahl, Jimmi Nielsen, Johannes J Struijk

Physiology of circulation, kidney and lung

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

37 Citationer (Scopus)

Abstract

Udgivelsesdato: 2009-Nov

Originalsprog	Engelsk
Tidsskrift	Journal of Clinical Pharmacology
Vol/bind	49
Udgave nummer	11
Sider (fra-til)	1331-42
Antal sider	11
ISSN	0091-2700
DOI	https://doi.org/10.1177/0091270009344853
Status	Udgivet - 2009

Bibliografisk note

Keywords: Adolescent; Adult; Delayed Rectifier Potassium Channels; Dihydropyridines; Drug Evaluation, Preclinical; Electrocardiography; Female; Heart Conduction System; Humans; Indoles; Male; Middle Aged; Models, Cardiovascular

Adgang til dokumentet

10.1177/0091270009344853

Citationsformater

Graff, C., Matz, J., Christensen, E. B., Andersen, M. P., Kanters, J. K., Toft, E., Pehrson, S., Hardahl, T. B., Nielsen, J., & Struijk, J. J. (2009). Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138. Journal of Clinical Pharmacology, 49(11), 1331-42. https://doi.org/10.1177/0091270009344853

Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138. / Graff, Claus; Matz, Jørgen; Christensen, Ellen B; Andersen, Mads P; Kanters, Jørgen K; Toft, Egon; Pehrson, Steen; Hardahl, Thomas B; Nielsen, Jimmi; Struijk, Johannes J.

I: Journal of Clinical Pharmacology, Bind 49, Nr. 11, 2009, s. 1331-42.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Graff, C, Matz, J, Christensen, EB, Andersen, MP, Kanters, JK, Toft, E, Pehrson, S, Hardahl, TB, Nielsen, J & Struijk, JJ 2009, 'Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138', Journal of Clinical Pharmacology, bind 49, nr. 11, s. 1331-42. https://doi.org/10.1177/0091270009344853

Graff, Claus ; Matz, Jørgen ; Christensen, Ellen B ; Andersen, Mads P ; Kanters, Jørgen K ; Toft, Egon ; Pehrson, Steen ; Hardahl, Thomas B ; Nielsen, Jimmi ; Struijk, Johannes J. / Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138. I: Journal of Clinical Pharmacology. 2009 ; Bind 49, Nr. 11. s. 1331-42.

@article{e5e4f4e0359911df8ed1000ea68e967b,

title = "Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138",

abstract = "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.",

author = "Claus Graff and J{\o}rgen Matz and Christensen, {Ellen B} and Andersen, {Mads P} and Kanters, {J{\o}rgen K} and Egon Toft and Steen Pehrson and Hardahl, {Thomas B} and Jimmi Nielsen and Struijk, {Johannes J}",

note = "Keywords: Adolescent; Adult; Delayed Rectifier Potassium Channels; Dihydropyridines; Drug Evaluation, Preclinical; Electrocardiography; Female; Heart Conduction System; Humans; Indoles; Male; Middle Aged; Models, Cardiovascular",

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doi = "10.1177/0091270009344853",

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T1 - Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138

AU - Graff, Claus

AU - Matz, Jørgen

AU - Christensen, Ellen B

AU - Andersen, Mads P

AU - Kanters, Jørgen K

AU - Toft, Egon

AU - Pehrson, Steen

AU - Hardahl, Thomas B

AU - Nielsen, Jimmi

AU - Struijk, Johannes J

N1 - Keywords: Adolescent; Adult; Delayed Rectifier Potassium Channels; Dihydropyridines; Drug Evaluation, Preclinical; Electrocardiography; Female; Heart Conduction System; Humans; Indoles; Male; Middle Aged; Models, Cardiovascular

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1177/0091270009344853

DO - 10.1177/0091270009344853

M3 - Journal article

C2 - 19843657

VL - 49

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JO - Journal of Clinical Pharmacology

JF - Journal of Clinical Pharmacology

SN - 0091-2700

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