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

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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.

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Acknowledgments

This study was sponsored by Wyeth Research, which was acquired by Pfizer Inc in October 2009. We thank all of the participants, research nurses, study coordinators, and operations staff who participated in this study. We also thank Christine H. Blood, PhD, of Peloton Advantage, LLC, for assistance with manuscript preparation, which was funded by Pfizer Inc.

Conflict of interest

At the time of this study, all authors were employees of Wyeth Pharmaceuticals. In addition, J. Boni, C. Leister, and D. Sonnichsen were stockholders in Wyeth.

Author information

Authors and Affiliations

  1. Clinical Pharmacology Lead, Pfizer Inc, 500 Arcola Road, Collegeville, PA, 19426, USA

    Joseph P. Boni

  2. Senior Principal Biostatistician II, Pfizer Inc, 500 Arcola Road, Collegeville, PA, 19426, USA

    Cathie Leister

  3. Medical Monitor, Pfizer Inc (Now: CSL Behring), 500 Arcola Road, Collegeville, PA, 19426, USA

    Bruce Hug

  4. Clinical Scientist, Pfizer Inc (Now: Teva), 500 Arcola Road, Collegeville, PA, 19426, USA

    Jaime Burns

  5. Clinical Pharmacology Team Lead, Pfizer Inc (Now: Sonnichsen Pharmaceutical Associates, L.L.C.), 500 Arcola Road, Collegeville, PA, 19426, USA

    Daryl Sonnichsen

Authors
  1. Joseph P. Boni
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  2. Cathie Leister
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  3. Bruce Hug
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  5. Daryl Sonnichsen
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Corresponding author

Correspondence to Joseph P. Boni.

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Boni, J.P., Leister, C., Hug, B. et al. A single-dose placebo- and moxifloxacin-controlled study of the effects of temsirolimus on cardiac repolarization in healthy adults. Cancer Chemother Pharmacol 69, 1433–1442 (2012). https://doi.org/10.1007/s00280-012-1845-7

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  • DOI: https://doi.org/10.1007/s00280-012-1845-7

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