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

Rashmi Shah

doi:10.5599/admet.4.3.295

Abstract

<p>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.</p>

Highlights

Treatment of various cancers has been significantly revolutionized by the development of small molecule protein kinase inhibitors (PKIs), a vast majority of them in current clinical use being tyrosine kinase inhibitors
This review aims to put in perspective the “QT-phobia” that surrounds the development of PKIs by highlighting just two of their other more serious and relatively more frequent cardiovascular effects, namely Left ventricular (LV) dysfunction and ATEs
The potential for clinically relevant hepatic injury is typically evaluated on the basis of the magnitude of increases in serum aspartate and alanine transaminases (AST and ALT), alkaline phosphatase (ALP) and bilirubin, the risk assessment and labelling are based on the number of cases that meet “Hy’s rule”

Summary

Introduction

Treatment of various cancers has been significantly revolutionized by the development of small molecule protein kinase inhibitors (PKIs), a vast majority of them in current clinical use being tyrosine kinase inhibitors. The perceived benefits of these highly targeted agents have led regulatory authorities to approve a majority of them on an expedited or priority basis, often on limited preliminary data indicative of their safety, efficacy and a favourable risk/benefit ratio [1,2,3]. Often, such approvals are associated with requirements for appropriate post-approval studies to substantiate these early expectations. The approval of many others has been either delayed or associated with prescribing restrictions in terms of narrow indication(s), contraindications and/or warnings and monitoring precautions [47]

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