A single supratherapeutic dose of ridaforolimus does not prolong the QTc interval in patients with advanced cancer
| Autor: | Richard Lush, Michele Trucksis, Keith Orford, Diana Selverian, K. Cerchio, Mark Stroh, John A. Wagner, Nancy G. B. Agrawal, Scot Ebbinghaus, Jacqueline B. McCrea, Marian Iwamoto, Amita Patnaik, Daniel C. Sullivan, Xiaodong Li, Kyriakos P. Papadopoulos, Anthony W. Tolcher |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
Male Oncology congenital hereditary and neonatal diseases and abnormalities Cancer Research medicine.medical_specialty mTOR inhibitor Pharmacology toxicology QTc interval Pharmacology Toxicology QT interval Ridaforolimus Electrocardiography chemistry.chemical_compound Neoplasms Internal medicine Humans Medicine Single-Blind Method Pharmacology (medical) In patient cardiovascular diseases Aged Sirolimus business.industry TOR Serine-Threonine Kinases Middle Aged Discovery and development of mTOR inhibitors Advanced cancer chemistry cardiovascular system Original Article Female Safety business circulatory and respiratory physiology |
| Zdroj: | Cancer Chemotherapy and Pharmacology |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-012-1942-7 |
| Popis: | 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 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. Electronic supplementary material The online version of this article (doi:10.1007/s00280-012-1942-7) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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