Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies

Daryl Sonnichsen, David J. Dorer, Jorge Cortes, Moshe Talpaz, Michael W. Deininger, Neil P. Shah, Hagop M. Kantarjian, Dale Bixby, Michael J. Mauro, Ian W. Flinn, Jeffrey Litwin, Christopher D. Turner, Frank G. Haluska

Research output: Contribution to journalArticle

Abstract

Purpose: Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial. Methods: Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points. Electrocardiographic parameters, including QTc interval, were measured, and 11 morphological analyses were conducted. Central tendency analyses of ECG parameters were performed using time-point and time-averaged approaches. All patients with at least 2 baseline ECGs and 1 on-treatment ECG were included in the analyses. Patients with paired ECGs and plasma samples were included in the pharmacokinetic/pharmacodynamic analysis to examine the relationship between ponatinib plasma concentration and change from baseline in QT intervals. Results: Thirty-nine patients at the 30-, 45-, and 60-mg dose levels were included in the central tendency and morphological analyses. There was no significant effect on cardiac repolarization, as evidenced by non-clinically significant mean QTcF changes from baseline of -10.9, -3.6, and -5.0 ms for the 30-, 45-, and 60-mg dose levels, respectively. The morphological analysis revealed 2 patients with atrial fibrillation and 2 with T wave inversion. Seventy-five patients were included in the pharmacokinetic/pharmacodynamic analysis across all dose levels. The slope of the relationship for QTcF versus plasma ponatinib concentration was not positive (-0.0171), indicating no exposure-effect relationship. Conclusions: Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.

Original languageEnglish (US)
Pages (from-to)1599-1607
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number6
DOIs
StatePublished - Jun 1 2013
Externally publishedYes

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Hematologic Neoplasms
Electrocardiography
Refractory materials
Pharmacodynamics
Pharmacokinetics
Plasmas
Protein-Tyrosine Kinases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
ponatinib
Atrial Fibrillation

Keywords

  • BCR-ABL
  • Chronic myeloid leukemia
  • Drug safety
  • Electrocardiography
  • Philadelphia chromosome
  • Ponatinib

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies. / Sonnichsen, Daryl; Dorer, David J.; Cortes, Jorge; Talpaz, Moshe; Deininger, Michael W.; Shah, Neil P.; Kantarjian, Hagop M.; Bixby, Dale; Mauro, Michael J.; Flinn, Ian W.; Litwin, Jeffrey; Turner, Christopher D.; Haluska, Frank G.

In: Cancer Chemotherapy and Pharmacology, Vol. 71, No. 6, 01.06.2013, p. 1599-1607.

Research output: Contribution to journalArticle

Sonnichsen, D, Dorer, DJ, Cortes, J, Talpaz, M, Deininger, MW, Shah, NP, Kantarjian, HM, Bixby, D, Mauro, MJ, Flinn, IW, Litwin, J, Turner, CD & Haluska, FG 2013, 'Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies', Cancer Chemotherapy and Pharmacology, vol. 71, no. 6, pp. 1599-1607. https://doi.org/10.1007/s00280-013-2160-7
Sonnichsen, Daryl ; Dorer, David J. ; Cortes, Jorge ; Talpaz, Moshe ; Deininger, Michael W. ; Shah, Neil P. ; Kantarjian, Hagop M. ; Bixby, Dale ; Mauro, Michael J. ; Flinn, Ian W. ; Litwin, Jeffrey ; Turner, Christopher D. ; Haluska, Frank G. / Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies. In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 71, No. 6. pp. 1599-1607.
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abstract = "Purpose: Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial. Methods: Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points. Electrocardiographic parameters, including QTc interval, were measured, and 11 morphological analyses were conducted. Central tendency analyses of ECG parameters were performed using time-point and time-averaged approaches. All patients with at least 2 baseline ECGs and 1 on-treatment ECG were included in the analyses. Patients with paired ECGs and plasma samples were included in the pharmacokinetic/pharmacodynamic analysis to examine the relationship between ponatinib plasma concentration and change from baseline in QT intervals. Results: Thirty-nine patients at the 30-, 45-, and 60-mg dose levels were included in the central tendency and morphological analyses. There was no significant effect on cardiac repolarization, as evidenced by non-clinically significant mean QTcF changes from baseline of -10.9, -3.6, and -5.0 ms for the 30-, 45-, and 60-mg dose levels, respectively. The morphological analysis revealed 2 patients with atrial fibrillation and 2 with T wave inversion. Seventy-five patients were included in the pharmacokinetic/pharmacodynamic analysis across all dose levels. The slope of the relationship for QTcF versus plasma ponatinib concentration was not positive (-0.0171), indicating no exposure-effect relationship. Conclusions: Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.",
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T1 - Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies

AU - Sonnichsen, Daryl

AU - Dorer, David J.

AU - Cortes, Jorge

AU - Talpaz, Moshe

AU - Deininger, Michael W.

AU - Shah, Neil P.

AU - Kantarjian, Hagop M.

AU - Bixby, Dale

AU - Mauro, Michael J.

AU - Flinn, Ian W.

AU - Litwin, Jeffrey

AU - Turner, Christopher D.

AU - Haluska, Frank G.

PY - 2013/6/1

Y1 - 2013/6/1

N2 - Purpose: Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial. Methods: Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points. Electrocardiographic parameters, including QTc interval, were measured, and 11 morphological analyses were conducted. Central tendency analyses of ECG parameters were performed using time-point and time-averaged approaches. All patients with at least 2 baseline ECGs and 1 on-treatment ECG were included in the analyses. Patients with paired ECGs and plasma samples were included in the pharmacokinetic/pharmacodynamic analysis to examine the relationship between ponatinib plasma concentration and change from baseline in QT intervals. Results: Thirty-nine patients at the 30-, 45-, and 60-mg dose levels were included in the central tendency and morphological analyses. There was no significant effect on cardiac repolarization, as evidenced by non-clinically significant mean QTcF changes from baseline of -10.9, -3.6, and -5.0 ms for the 30-, 45-, and 60-mg dose levels, respectively. The morphological analysis revealed 2 patients with atrial fibrillation and 2 with T wave inversion. Seventy-five patients were included in the pharmacokinetic/pharmacodynamic analysis across all dose levels. The slope of the relationship for QTcF versus plasma ponatinib concentration was not positive (-0.0171), indicating no exposure-effect relationship. Conclusions: Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.

AB - Purpose: Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial. Methods: Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points. Electrocardiographic parameters, including QTc interval, were measured, and 11 morphological analyses were conducted. Central tendency analyses of ECG parameters were performed using time-point and time-averaged approaches. All patients with at least 2 baseline ECGs and 1 on-treatment ECG were included in the analyses. Patients with paired ECGs and plasma samples were included in the pharmacokinetic/pharmacodynamic analysis to examine the relationship between ponatinib plasma concentration and change from baseline in QT intervals. Results: Thirty-nine patients at the 30-, 45-, and 60-mg dose levels were included in the central tendency and morphological analyses. There was no significant effect on cardiac repolarization, as evidenced by non-clinically significant mean QTcF changes from baseline of -10.9, -3.6, and -5.0 ms for the 30-, 45-, and 60-mg dose levels, respectively. The morphological analysis revealed 2 patients with atrial fibrillation and 2 with T wave inversion. Seventy-five patients were included in the pharmacokinetic/pharmacodynamic analysis across all dose levels. The slope of the relationship for QTcF versus plasma ponatinib concentration was not positive (-0.0171), indicating no exposure-effect relationship. Conclusions: Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.

KW - BCR-ABL

KW - Chronic myeloid leukemia

KW - Drug safety

KW - Electrocardiography

KW - Philadelphia chromosome

KW - Ponatinib

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