Abstract
PurposeCardiac 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.MethodsElectrocardiograms (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.ResultsThirty-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.ConclusionsPonatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.
Highlights
Ponatinib (AP24534) is a novel, synthetic, orally administered, multi-targeted tyrosine kinase inhibitor (TKI) and a potent pan–BCR-ABL inhibitor [1–3]
This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial
Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies
Summary
Ponatinib (AP24534) is a novel, synthetic, orally administered, multi-targeted tyrosine kinase inhibitor (TKI) and a potent pan–BCR-ABL inhibitor [1–3]. The product of a computational and structure-based approach to the design of a small-molecule TKI, ponatinib binds with high affinity to the active site of BCR-ABL and renders binding less susceptible to any single amino acid substitution [1]. Based on the results in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia ALL) in phase 1 testing and phase 2 clinical trials [4, 5], ponatinib (45 mg once daily) has been approved in the United States for the treatment of patients with CML and Ph? Cardiac dysfunction has been noted with other TKIs approved for the treatment of patients with CML. The imatinib prescribing information includes a warning regarding congestive heart failure and left ventricular dysfunction [7]. During phase 1 testing of ponatinib, treatment-related QTc prolongation was observed in 4 % of patients [4]
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