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A single supratherapeutic dose of ridaforolimus does not prolong the QTc interval in patients with advanced cancer.

Abstract：

PURPOSE:This 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. METHODS:We 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). RESULTS:The 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. CONCLUSIONS:Administration 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.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Lush RM,Patnaik A,Sullivan D,Papadopoulos KP,Trucksis M,McCrea J,Cerchio K,Li X,Stroh M,Selverian D,Orford K,Ebbinghaus S,Agrawal N,Iwamoto M,Wagner JA,Tolcher A

doi

10.1007/s00280-012-1942-7

subject

Has Abstract

pub_date

2012-10-01 00:00:00

pages

567-74

issue

eissn

0344-5704

issn

1432-0843

journal_volume

pub_type

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A single supratherapeutic dose of ridaforolimus does not prolong the QTc interval in patients with advanced cancer.