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

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.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…QTc prolongation was common (37%) in patients with hepatic impairment treated with bosutinib,10 but this was not seen in other smaller studies 11, 12. QTc prolongation was infrequent or absent with afatinib, crizotinib, ceritinib, dovitinib, imatinib, lapatinib, lenvatinib, nintedanib, pazopanib, and ponatinib 9, 14, 16, 17, 19, 24, 26, 27, 29, 30, 31, 32, 33, 35, 36, 38, 39, 72, 78, 81, 161, 162, 163, 164…”

Deep Learning-Based Prediction of Drug-Induced Cardiotoxicity

“…An in vitro assay conducted in human embryonic kidney cells stably expressing the hERG potassium channel revealed that ponatinib inhibits hERG at a concentration above 1 μM. 55 Vandetanib, a multi-kinase inhibitor approved for treatment of multiple cancer types, has been reported to inhibit the hERG at 3 μM detected by a whole-cell patch-clamp assay in transiently transfected HEK293 cells. 56 Finally, several new deephERG-predicted TKIs without literature data also need to be highly vigilant, such as bosutinib, gefitinib, afatinib and dasatinib, which are warranted by experimental or clinical validation in the future.…”

Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs

“…Notably, the diagnosis was suggested only by echocardiogram in 5 of the 9 patients with this finding; catheterization was only performed (and confirmed the diagnosis) in 4 patients. The overall frequencies of vascular 5,[11][12][13][14][15][16][17][18]37 and cardiac [19][20][21][22][23][24][25][26] AEs varied across various clinical trials depending on the study design, type of TKI, treatment durations, AE definitions, and eligibility criteria. Contrary to some reports, 38 we observed that dasatinib was associated with a higher risk of AT-AE relative to imatinib, with a risk that appears similar to that with nilotinib.…”

“…The 8-year probability of grade 3-4 cardiac, vascular, or congestive heart failure (CHF) AEs with imatinib was 0.5%, 0.3%, or 3.1%, respectively. 10 The relative frequencies of vascular 5,[11][12][13][14][15][16][17][18] and cardiac [19][20][21][22][23][24][25][26] AEs with the different TKIs are difficult to estimate based on the literature because different reports have used different methods for analysis, and what events are included in the general category of "arteriothrombotic events" vary widely, with some reports analyzing a few hundred medical dictionary for regulatory activities (MeDRA) terms while others focus only on specific confirmed diagnosis.…”