A single supratherapeutic dose of ridaforolimus does not prolong the QTc interval in patients with advanced cancerReport as inadecuate




A single supratherapeutic dose of ridaforolimus does not prolong the QTc interval in patients with advanced cancer - Download this document for free, or read online. Document in PDF available to download.

Cancer Chemotherapy and Pharmacology

, Volume 70, Issue 4, pp 567–574

First Online: 10 August 2012Received: 30 May 2012Accepted: 23 July 2012

Abstract

PurposeThis dedicated QTc study was designed to evaluate the effect of the mammalian target of rapamycin inhibitor, ridaforolimus, on the QTc interval in patients with advanced malignancies.

MethodsWe conducted a fixed-sequence, single-blind, placebo-controlled study. Patients n = 23 received placebo on day 1 and a single 100-mg oral dose of ridaforolimus on day 2 in the fasted state. Holter electrocardiogram ECG monitoring was performed for 24 h after each treatment, and blood ridaforolimus concentrations were measured for 24 h after dosing. The ECGs were interpreted in a blinded fashion, and the QT interval was corrected using Fridericia’s formula QTcF. After a washout of at least 5 days, 22 patients went on to receive a therapeutic regimen of ridaforolimus 40 mg orally once daily for 5 days per week.

ResultsThe upper limit of the two-sided 90 % confidence interval for the placebo-adjusted mean change from baseline in QTcF was <10 ms at each time point. No patient had a QTcF change from baseline >30 ms or QTcF interval >480 ms. Geometric mean exposure to ridaforolimus after the single 100-mg dose was comparable to previous experience with the therapeutic regimen. There appeared to be no clear relationship between individual QTcF change from baseline and ridaforolimus blood concentrations. Ridaforolimus was generally well tolerated, with adverse events consistent with prior studies.

ConclusionsAdministration of the single 100-mg dose of ridaforolimus did not cause a clinically meaningful prolongation of QTcF, suggesting that patients treated with ridaforolimus have a low likelihood of delayed ventricular repolarization.

KeywordsRidaforolimus mTOR inhibitor QTc interval Safety Electronic supplementary materialThe online version of this article doi:10.1007-s00280-012-1942-7 contains supplementary material, which is available to authorized users.

Download fulltext PDF



Author: Richard M. Lush - Amita Patnaik - Daniel Sullivan - Kyriakos P. Papadopoulos - Michele Trucksis - Jacqueline McCrea - Kris

Source: https://link.springer.com/







Related documents