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

Richard M Lush, Amita Patnaik, Daniel Sullivan, Kyriakos P Papadopoulos, Michele Trucksis, Jacqueline McCrea, Kristine Cerchio, Xiaodong Li, Mark Stroh, Diana Selverian, Keith Orford, Scot Ebbinghaus, Nancy Agrawal, Marian Iwamoto, John A Wagner, Anthony Tolcher, Richard M Lush, Amita Patnaik, Daniel Sullivan, Kyriakos P Papadopoulos, Michele Trucksis, Jacqueline McCrea, Kristine Cerchio, Xiaodong Li, Mark Stroh, Diana Selverian, Keith Orford, Scot Ebbinghaus, Nancy Agrawal, Marian Iwamoto, John A Wagner, Anthony Tolcher

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.

Figures

Fig. 1
Fig. 1
a Arithmetic mean blood concentration–time profile after oral administration of single 100-mg dose of ridaforolimus to patients with advanced cancer (n = 21). One patient was excluded from average blood concentration profile due to a protocol violation. b Placebo-adjusted means and 90 % confidence intervals (CIs) for change from baseline of Fridericia-corrected QTc (QTcF) intervals. The upper limit of the 90 % CI for the placebo-adjusted mean change from baseline in QTcF was <10 ms at each time point, indicating that ridaforolimus did not prolong the QTcF interval
Fig. 2
Fig. 2
Individual QTc change from baseline versus ridaforolimus blood concentration after oral administration of single 100-mg dose of ridaforolimus to patients with advanced cancer. No clear relationship was evident between the individual Fridericia-corrected QTc (QTcF) changes from baseline and ridaforolimus blood concentrations

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