A single-dose placebo- and moxifloxacin-controlled study of the effects of temsirolimus on cardiac repolarization in healthy adults.

Abstract

PURPOSE:

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: Joseph P Boni, Cathie Leister, Bruce Hug, Jaime Burns, Daryl Sonnichsen
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 69 Issue 6 Pg. 1433-42 (Jun 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 22367193 (Publication Type: Controlled Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Infective Agents
• Antineoplastic Agents
• Aza Compounds
• Cytochrome P-450 CYP3A Inhibitors
• Fluoroquinolones
• Placebos
• Protein Kinase Inhibitors
• Quinolines
• temsirolimus
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Moxifloxacin
• Sirolimus

Topics

• Adolescent
• Adult
• Anti-Infective Agents (pharmacology)
• Antineoplastic Agents (pharmacology)
• Aza Compounds (pharmacology)
• Cross-Over Studies
• Cytochrome P-450 CYP3A
• Cytochrome P-450 CYP3A Inhibitors
• Electrocardiography (drug effects)
• Female
• Fluoroquinolones
• Humans
• Male
• Middle Aged
• Moxifloxacin
• Placebos
• Protein Kinase Inhibitors (pharmacology)
• Quinolines (pharmacology)
• Single-Blind Method
• Sirolimus (adverse effects, analogs & derivatives, pharmacokinetics, pharmacology)