title: A single supratherapeutic dose of ridaforolimus does not prolong the QTc interval in patients with advanced cancer.
abstract: OBJECTIVE
  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.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. richard.lush@moffitt.org
authors.forename: Richard M
authors.initials: RM
authors.lastname: Lush
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Daniel
authors.initials: D
authors.lastname: Sullivan
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Michele
authors.initials: M
authors.lastname: Trucksis
authors.forename: Jacqueline
authors.initials: J
authors.lastname: McCrea
authors.forename: Kristine
authors.initials: K
authors.lastname: Cerchio
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Mark
authors.initials: M
authors.lastname: Stroh
authors.forename: Diana
authors.initials: D
authors.lastname: Selverian
authors.forename: Keith
authors.initials: K
authors.lastname: Orford
authors.forename: Scot
authors.initials: S
authors.lastname: Ebbinghaus
authors.forename: Nancy
authors.initials: N
authors.lastname: Agrawal
authors.forename: Marian
authors.initials: M
authors.lastname: Iwamoto
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D016037:Single-Blind Method; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C515074:ridaforolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus