title: A single-dose placebo- and moxifloxacin-controlled study of the effects of temsirolimus on cardiac repolarization in healthy adults.
abstract: OBJECTIVE
  Temsirolimus, a selective inhibitor of mammalian target of rapamycin, is an approved treatment for patients with advanced renal cell carcinoma (RCC). This study assessed the effect of intravenous (i.v.) temsirolimus 25 mg, the recommended dose for patients with RCC, on the corrected QT (QTc) interval.
  
  
  METHODS
  This 3-period crossover study enrolled healthy subjects. In periods 1 and 2, subjects received i.v. placebo either alone or with open-label oral moxifloxacin. In period 3, subjects received a single dose of temsirolimus 25 mg. The primary statistical objective was to estimate the effect of temsirolimus compared with placebo on change from time-matched baseline QTc at the end of infusion (0.5 h). Assay sensitivity was evaluated by the effect of moxifloxacin on change from time-matched baseline QTc compared with placebo.
  
  
  RESULTS
  In total, 58 subjects were enrolled. Temsirolimus had no effect on QTc interval in the primary analysis. At 11 of 12 secondary time points, the upper bound for the temsirolimus QTc 90% confidence intervals for the time-matched change from baseline difference from placebo was <10 ms, with no evidence of QTc trends or relationship to concentrations of temsirolimus or its major metabolite, sirolimus. Moxifloxacin, the positive control, produced a significant increase in the QTc interval compared with placebo 0.5-4 h post-dose (P < 0.0001). No subject had a QTc interval exceeding 450 ms or a change from baseline of >30 ms.
  
  
  CONCLUSIONS
  Therapeutic exposure to temsirolimus is not associated with clinically significant changes in QTc intervals in healthy adults.
authors.affiliation: Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426, USA. Joseph.Boni@pfizer.com
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Boni
authors.forename: Cathie
authors.initials: C
authors.lastname: Leister
authors.forename: Bruce
authors.initials: B
authors.lastname: Hug
authors.forename: Jaime
authors.initials: J
authors.lastname: Burns
authors.forename: Daryl
authors.initials: D
authors.lastname: Sonnichsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010919:Placebos; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D016037:Single-Blind Method; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D001372:Aza Compounds; D065692:Cytochrome P-450 CYP3A Inhibitors; D024841:Fluoroquinolones; D010919:Placebos; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C401859:temsirolimus; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077266:Moxifloxacin; D020123:Sirolimus