Abstract
PurposeLinifanib is a selective inhibitor of the vascular endothelial growth factor and platelet-derived growth factor family of tyrosine kinase inhibitors. The purpose of this high-precision QT study was to evaluate the effects of linifanib on cardiac repolarization in patients with advanced metastatic tumors.MethodsEnrolled patients (n = 24) had measurable disease refractory to standard therapies, ECOG performance status of 0–1, and adequate organ function. Patients were randomized in a 2-sequence, 2-period crossover design. Serial ECG measurements and pharmacokinetic samples were collected for each crossover period. An intersection–union test was performed for time-matched baseline-adjusted QTcF intervals. An exposure–response analysis was explored to correlate the plasma concentration and QTcF.ResultsThe maximum 95 % upper confidence bound for the baseline-adjusted QTcF was 4.3 ms at hour 3 at the maximum tolerated linifanib dose of 0.25 mg/kg. Linifanib did not meet the regulatory threshold (10 ms) for QT prolongation. Exposure–response modeling showed that the QTcF change was not significant at the maximum plasma concentration.ConclusionsLinifanib does not significantly affect cardiac repolarization in patients with advanced solid tumors.
Highlights
Cardiac safety has become a vital issue for cancer patients as life expectancies are increased with emerging therapies
The maximum 95 % upper confidence bound for the drug effects for linifanib was 4.30 ms
Analysis was performed with linifanib concentration as the drug exposure variable
Summary
Cardiac safety has become a vital issue for cancer patients as life expectancies are increased with emerging therapies. Cancer therapy is becoming increasingly specialized, having evolved from using cytotoxic drugs on dividing cells to targeting specific molecular events involved in oncogenic proliferation. Among these targeted therapeutics is a drug class known as tyrosine kinase inhibitors (TKIs). Tyrosine kinases are enzymes that catalyze phosphorylation of target proteins, signaling cellular processes such as growth and proliferation. Unregulated tyrosine kinase activation, can cause uncontrolled cellular proliferation, leading to cancer. Complete inhibition of tyrosine kinases may disrupt vital cellular signaling, targeted TKIs may prevent cancerous proliferation while sparing essential kinase activity [1, 2]
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