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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-012-1942-7) contains supplementary material, which is available to authorized users.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.A
Administration of the single 100-mg dose of ridaforolimus did not cause a clinically meaningful prolongation of QT interval was corrected using Fridericia’s formula (QTcF), suggesting that patients treated with ridaforolimus have a low likelihood of delayed ventricular repolarization
confidence intervals (CIs) confidence interval, AUC0-24 area under the concentration–time curve from zero to 24 h, Cmax maximum concentration, Tmax time to maximum concentration a Median for Tmax one patient experienced a QTc interval [450 ms. This patient had day 1 QTcF values of 459.8, 453.8, 454.6, 450.4, and 451.2 ms at predose, 0.5 h after placebo, 1 h after placebo, 2 h after placebo, and 3 h after placebo, All 23 patients enrolled were evaluated for safety in part 1 after receiving placebo; the 22 patients who received ridaforolimus in part 1 of the study and subsequently entered part 2 were included in the safety evaluation
Summary
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. 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. 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
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