ADMET and DMPK  

Cardiovascular safety of tyrosine kinase inhibitors: Putting their “QT-phobia” in perspective

Rashmi Shah

Abstract


Many potentially valuable drugs, including protein kinase inhibitors (PKI), risk being dropped from further development, without exploration of their clinical benefits, if early studies show these drugs to inhibit hERG channel and therefore, to have a potential for prolonging ventricular repolarisation (QT interval). This QT-phobia results from a perceived possibility of the clinical risks of QT-related ventricular proarrhythmia, further aggravated by uncertainties surrounding the regulatory evaluation of the risk and either approvability or restrictive labelling of the drug concerned. In reality, QT interval prolongation per se is only an imperfect surrogate of the proarrhythmia risk which is much smaller than perceived and compared to their other cardiovascular and non-cardiovascular risks. PKI-induced clinical hepatotoxicity, also evaluated on the basis of surrogate markers (serum transaminases and bilirubin) is another risk that far exceeds any risk arising from PKI-induced QT interval prolongation. This review of the currently approved 28 PKIs places the QT-phobia surrounding the development of PKIs in its perspective by juxta-positioning their potential to induce ventricular dysfunction, arterial thrombotic events and hepatotoxicity. Available evidence suggests that hERG channel may prove to be a valuable therapeutic target in oncology. Therefore, the development, approval and labelling of such vital oncology drugs requires careful assessment of their benefits and their risk/benefit generally, without being overtly consumed by their potential QT-liability, in terms of their more direct consequences on clinically relevant endpoints of morbidity, mortality and quality of life.


Keywords


Arterial thrombotic events; Cardiotoxicity; Hepatotoxicity; hERG channel; Left ventricular dysfunction; Proarrhythmias; QT interval; Transaminases; Torsade de pointes; Tyrosine kinase inhibitors

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DOI: http://dx.doi.org/10.5599/admet.4.3.295

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ISSN 1848-7718